Increased specific T cell cytokine responses in patients with active pulmonary tuberculosis from Central Africa

An understanding of T cell responses that are crucial for control of Mycobacterium tuberculosis (MTB) has major implications for the development of immune-based interventions. We studied the frequency of purified protein derivative (PPD)-specific CD3) cells expressing interleukin-2 (IL)-2, gamma interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and IL-10 in HIV-negative pulmonary tuberculosis patients (TB, n=30) as well as in healthy individuals (controls, n=21) from Central Africa. Increased frequencies of PPD-stimulated CD3+ cells expressing IL-2, IFN-gamma, and TNF-alpha in TB were seen when compared with frequencies of controls. The presence of type 1 cytokine biased responses in TB patients was supported by a shift in the distribution pattern of cytokine expression from exclusively IL-2 or TNF-alpha expression seen in controls towards an increased frequency of IFN-gamma/IL-2 or IFN-gamma/TNF-alpha co-expression in TB. Higher levels of PPD-induced IFN-gamma in the supernatants from TB patients than from controls were found, which correlated with its intracellular expression. PPD was a weak inducer of IL-10 in T cells and insufficient in promoting cytokine production in TCRgammadelta+CD3+ cells. Non-specific stimulation with PMA and ionomycin revealed increased frequencies of CD4+ cells expressing IFN-gamma in controls, while expression of IL-2, IL-4, IL-10, IL-13, and TNF-alpha was not different. Non-specific cytokine responses of TCRgammadelta+CD3+ cells were similar in all groups. Pulmonary TB in Central Africa is associated with enhanced expression and secretion of specifically induced cytokines that are frequently implicated in host defense against MTB.     

Altered cytokine responses of dengue-specific CD4+ T cells to heterologous serotypes

The interplay of different inflammatory cytokines induced during a dengue (DEN) virus infection plays a role in either protection or increased disease severity. We measured the frequencies and characterized the cytokine responses of DEN virus-specific memory CD4+ T cells in PBMC of six volunteers who received experimental live attenuated monovalent DEN vaccines. IFN-gamma and TNF-alpha responses to inactivated DEN Ags were detected in up to 0.54 and 1.17% of total circulating CD4+ T cells, respectively. Ags from the homologous serotype elicited the highest IFN-gamma response. The ratio of TNF-alpha- to IFN-gamma-producing CD4+ T cells was higher after stimulation with Ags from heterologous DEN serotypes. Peptide-specific CD4+ T cell frequencies of up to 0.089% were detected by direct staining using HLA class II tetramers. IFN-gamma and TNF-alpha responses to individual HLA class II-restricted peptide epitopes were detected in up to 0.05 and 0.27% of CD4+ T cells, respectively. Peptide sequences from the homologous serotype elicited a variety of cytokine response patterns. TNF-alpha- to IFN-gamma-positive CD4+ T cell ratios varied between peptides, but the ratio of the sum of responses was highest against heterologous serotypes. These results demonstrate epitope sequence-specific differences in T cell effector function. These patterns of effector responses may play a role in the immunopathogenesis of DEN hemorrhagic fever.     

Naturally acquired CD8+ cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein.

In rodent malaria model systems, protective immunity induced by immunization with irradiated sporozoites is eliminated by in vivo depletion of CD8+ T cells, and adoptive transfer of CTL clones against the circumsporozoite protein protects against malaria. We recently demonstrated that volunteers immunized with irradiated Plasmodium falciparum sporozoites produce CTL against peptide 368-390 of the P. falciparum circumsporozoite protein. To determine whether natural exposure to malaria induced similar CTL, we studied 11 adult, male, life-long residents of a highly malarious area of Kenya, who were selected because their lymphocytes had been shown to proliferate after stimulation with peptides 361-380, 371-390, or 368-390 and because nine had been resistant to malaria in previous studies. In four of the 11 individuals there was peptide-specific, genetically restricted, CTL activity. In all four individuals, this activity was unaffected by depletion of CD4+ T cells. In three volunteers the activity was eliminated or reduced by depletion of CD8+ T cells; in the fourth volunteer the CD8+ T cell depletion was uninterpretable. This first demonstration of CD8+ T cell, genetically restricted, Ag-specific CTL against a malaria protein among individuals exposed to endemic malaria provides a foundation for studying the relationship between circulating CTL and resistance to malaria infection.     

Crosslinking CD81 results in activation of TCRgammadelta T cells

CD81 is expressed on most cells and is associated with other glycoproteins, including CD4 and CD8, to form multimolecular membrane complexes. Crosslinking of CD81 on TCRalphabeta(+) T cells results in costimulatory signals that have been proposed to be mediated via CD4 or CD8. In this study, we show that CD81 is also expressed on TCRgammadelta(+)CD4(-)CD8(-) T cells. CD81 crosslinking greatly enhanced anti-CD3 activation of both TCRalphabeta(+) (CD4+ and CD8+) and TCRgammadelta(+) T cells with regard to IFN-gamma production. However, crosslinking of CD81 molecules on TCRgammadelta(+) T cells, in the absence of anti-CD3 stimulation, resulted in cytokine production and enhanced IL-2-induced proliferation, demonstrating that physical association with CD4 or CD8 is not necessary for CD81 signaling. In contrast, crosslinking of CD81 on TCRalphabeta(+) T cells, in the absence of anti-CD3 stimulation, failed to activate these T cells. These results suggest that CD81 signaling may be mediated via a different mechanism(s) in TCRgammadelta(+) versus TCRalphabeta(+) T cells.     

TCR gamma delta+ and CD161+ thymocytes express HIV-1 in the SCID-hu mouse,potentially contributing to immune dysfunction in HIV infection

The vast diversity of the T cell repertoire renders the adaptive immune response capable of recognizing a broad spectrum of potential antigenic peptides. However, certain T cell rearrangements are conserved for recognition of specific pathogens, as is the case for TCRgammadelta cells. In addition, an immunoregulatory class of T cells expressing the NK receptor protein 1A (CD161) responds to nonpeptide Ags presented on the MHC-like CD1d molecule. The effect of HIV-1 infection on these specialized T cells in the thymus was studied using the SCID-hu mouse model. We were able to identify CD161-expressing CD3(+) cells but not the CD1d-restricted invariant Valpha24/Vbeta11/CD161(+) NK T cells in the thymus. A subset of TCRgammadelta cells and CD161-expressing thymocytes express CD4, CXCR4, and CCR5 during development in the thymus and are susceptible to HIV-1 infection. TCRgammadelta thymocytes were productively infectable by both X4 and R5 virus, and thymic HIV-1 infection induced depletion of CD4(+) TCRgammadelta cells. Similarly, CD4(+)CD161(+) thymocytes were depleted by thymic HIV-1 infection, leading to enrichment of CD4(-)CD161(+) thymocytes. Furthermore, compared with the general CD4-negative thymocyte population, CD4(-)CD161(+) NK T thymocytes exhibited as much as a 27-fold lower frequency of virus-expressing cells. We conclude that HIV-1 infection and/or disruption of cells important in both innate and acquired immunity may contribute to the overall immune dysfunction seen in HIV-1 disease.     

Role of sulfation in CD44-mediated hyaluronan binding induced by inflammatory mediators in human CD14(+) peripheral blood monocytes.

Activation of T cells by Ag or stimulation of monocytes with inflammatory cytokines induces CD44 to bind to hyaluronan (HA), an adhesion event implicated in leukocyte-leukocyte, leukocyte-endothelial cell, and leukocyte-stromal cell interactions. We have previously shown that TNF-alpha induces CD44 sulfation in a leukemic cell line, which correlated with the induction of HA binding and CD44-mediated adhesion. In this study, we establish that TNF-alpha and IFN-gamma induce HA binding and the sulfation of CD44 in CD14(+) PBMC, whereas no induced HA binding or CD44 sulfation was observed in CD14(-) PBMC stimulated with TNF-alpha. Treatment of cells with NaClO(3), an inhibitor of sulfation, prevented HA binding in a significant percentage of CD14(+) PBMC induced by TNF-alpha, LPS, IL-1beta, or IFN-gamma. Furthermore, stimulation with TNF-alpha or IFN-gamma in the presence of NaClO(3) reduced the ability of isolated CD44H to bind HA, demonstrating a direct effect of CD44H sulfation on HA binding. In contrast, the transient induction of HA binding in T cells by PHA was not affected by NaClO(3), suggesting that activated T cells do not use sulfation as a mechanism to regulate HA binding. Overall, these results demonstrate that inducible sulfation of CD44H is one mechanism used by CD14(+) peripheral blood monocytes to induce HA binding in response to inflammatory agents such as TNF-alpha and IFN-gamma.     

Leptospira interrogans activation of human peripheral blood mononuclear cells: preferential expansion of TCR gamma delta+ T cells vs TCR alpha beta+ T cells

Innate and adaptive immune responses induced by leptospirosis have not been well characterized. In this study we show that in vitro exposure of naive human PBMC to Leptospira interrogans results in cell proliferation and the production of IFN-gamma, IL-12, and TNF-alpha. Cell proliferation was highest when using high numbers of Leptospira. Optimal cell proliferation occurred at 6-8 days, and the majority of cells contained in these cultures were gamma/delta T cells. These cultures showed a 10- to 50-fold expansion of gamma/delta T cells compared with the initial cellular input. Additionally, these cultures contained elevated numbers of NK cells. In contrast, exposure of PBMC to low numbers of Leptospira failed to induce gammadelta T cell or NK cell expansion, but induced significant alphabeta T cell expansion. Vgamma9/Vdelta2 were expressed on all gamma/delta T cells expanded by exposure of PBMC to Leptorspira: Leptospira stimulation of purified TCRgammadelta(+) T cells, obtained from 8-day cultures of Leptospira-stimulated PBMC, induced high levels of IFN-gamma production, but no cell proliferation, suggesting that such stimulation of gammadelta T cells did not depend on specialized accessory cells or Ag processing. Finally, in patients with acute leptospirosis, there was a significant (4- to 5-fold) increase in the number of peripheral blood TCRgammadelta(+) T cells. These results indicate that Leptospira can activate gammadelta T cells and alphabeta T cells and will guide further investigations into the roles of these T cell populations in host defense and/or the pathology of leptospirosis.     

The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns.

The human liver contains significant numbers of T cells, NK cells, and lymphocytes that coexpress T and NK cell receptors. To evaluate their functional activities, we have compared the cytotoxic activities and cytokines produced by normal adult hepatic CD3+CD56- (T) cells, CD3-CD56+ (NK) cells, and CD3+CD56+ (natural T (NT)) cells. In cytotoxicity assays using immunomagnetic bead-purified NK cell, T cell, and NT cell subpopulations as effectors, fresh hepatic NK cells lysed K562 targets, while NT cells could be induced to do so by culturing with IL-2. Both NT and T cells were capable of redirected cytolysis of P815 cells using Abs to CD3. Flow cytometric analysis of cytokine production by fresh hepatic lymphocyte subsets activated by CD3 cross-linking or PMA and ionomycin stimulation indicated that NT cells and T cells could produce IFN-gamma, TNF-alpha, IL-2, and/or IL-4, but little or no IL-5, while NK cells produced IFN-gamma and/or TNF-alpha only. The majority of NT cells produced inflammatory (Th1) cytokines only; however, approximately 6% of all hepatic T cells, which included 5% of Valpha24 TCR-bearing NT cells and 2% of gammadeltaTCR+ cells, simultaneously produced IFN-gamma and IL-4. The existence of such large numbers of cytotoxic lymphocytes with multiple effector functions suggests that the liver is an important site of innate immune responses, early regulation of adaptive immunity, and possibly peripheral deletion of autologous cells.     

TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses

Many mechanisms involving TNF-alpha, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-alpha to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14(+) monocytes cultured in the presence of TNF-alpha and GM-CSF converted to CD14(+) CD1a(low) adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-alpha, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (M phi). The mature DC (CD83(+) CD70(+) HLA-DR (high) CD14(low)) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-gamma and TNF-alpha, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-alpha added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the M phi (CD14(high)CD70(+)CD83(-)HLA-DR(-)) produced large amounts of MMP-9 and TNF-alpha without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated M phi. Therefore, additional stimulation of monocytes with TNF-alpha may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated M phi-mediated innate immunity.     

Plasmodium falciparum liver-stage antigen-1 peptide-specific interferon-gamma responses are not suppressed during uncomplicated malaria in African children.

Liver-stage antigen (LSA)-1 is a candidate vaccine molecule for Plasmodium falciparum malaria, but knowledge of the evolution of naturally acquired immune responses to LSA-1 in African children is lacking. We therefore assessed cellular immune responses to two defined T cell epitopes of LSA-1, during and after uncomplicated P. falciparum malaria in a group of Gabonese children. In terms of their prevalence, interferon (IFN)-gamma responses of peripheral blood mononuclear cells (PBMC) to an LSA-1 N-terminal peptide, T1, were significantly higher when measured during the acute phase compared with convalescence. IFN-gamma responses to the LSA-J (hinge region) peptide showed a similar profile, but at a lower prevalence. Depletion experiments confirmed that CD8+ T cells are a major source of peptide-driven IFN-gamma, but both lymphoproliferation and the production of IL-10 in response to either of the peptides was low in all children at all times. PBMC from 25% of the children failed to produce IFN-gamma in response to either peptide at any time-point. The results suggest that lymphocytes producing IFN-gamma in response to at least one T cell epitope of LSA-1 are most frequent in the peripheral circulation during the acute phase of P. falciparum malaria. Thus, in this case, the generalised suppression of cell-mediated responses which characterises acute malaria does not affect liver-stage antigen-specific IFN-gamma production. These findings imply that measurements of the frequency of parasite antigen-specific cellular immune responses in clinically healthy individuals may represent significant underestimations, which has important implications for the design of field-based vaccine antigen-related studies.     

CD8+ cytotoxic T-APC stimulate central memory CD8+ T cell responses via acquired peptide-MHC class I complexes and CD80 costimulation, and IL-2 secretion

We previously showed that naive CD4+ Th cells acquire peptide-MHC class I (pMHC I) and costimulatory molecules from OVA-pulsed dendritic cells (DC(OVA)), and act as Th-APCs in stimulation of CD8+ CTL responses. In this study, we further demonstrated that naive CD8+ cytotoxic T (Tc) cells also acquire pMHC I and costimulatory CD54 and CD80 molecules by DC(OVA) stimulation, and act as Tc-APC. These Tc-APC can play both negative and positive modulations in antitumor immune responses by eliminating DC(OVA) and neighboring Tc-APC, and stimulating OVA-specific CD8+ central memory T responses and antitumor immunity. Interestingly, the stimulatory effect of Tc-APC is mediated via its IL-2 secretion and acquired CD80 costimulation, and is specifically targeted to OVA-specific CD8+ T cells in vivo via its acquired pMHC I complexes. These principles could be applied to not only antitumor immunity, but also other immune disorders (e.g., autoimmunity).     

Defective production of and response to IL-2 in acute human falciparum malaria

Patients with acute Plasmodium falciparum malaria have defective cell-mediated immune responses to malaria-specific Ag (MA). This immunologic defect may partially explain the difficulty with which natural immunity to falciparum malaria develops and may have important implications for the efficacy of potential malaria vaccines in endemic areas. To investigate the basis of this immune defect, we have examined the capacity of PBMC from patients with acute falciparum malaria to produce IL-2 and to express I1-2R in response to Ag stimulation. The effect of exogenous IL-1 and IL-2 on lymphocyte proliferation was studied. Soluble IL-2R levels were measured in acute and convalescent sera. Our results showed that no detectable IL-2 was produced and no IL-2R were expressed by PBMC in response to MA during the acute infection. IL-2 production and IL-2R expression were also depressed when PBMC were exposed to streptococcal Ag. The specific immune defect was not reconstituted by the addition of graded doses of purified human IL-1 or IL-2 and could not be attributed to suppressor adherent cells. In contrast to the absence of IL-2 and cell-bound IL-2R, circulating soluble IL-2R was elevated in acute sera. These findings suggest that the lack of IL-2, through either a defect in its production or inhibition of its activity, may be the basis of the Ag-specific immune unresponsiveness in acute P. falciparum malaria.     

TNF-alpha antagonism generates a population of antigen-specific CD4+CD25+ T cells that inhibit protective immunity in murine histoplasmosis

In both humans and mice, treatment with TNF-alpha antagonists is associated with serious infectious complications including disseminated histoplasmosis. The mechanisms by which inhibition of endogenous TNF-alpha alter protective immunity remain obscure. Herein, we tested the possibility that neutralization of this cytokine triggered the emergence of T cells that dampen immunity. The lungs of mice given mAb to TNF-alpha contained a higher proportion and number of CD4+CD25+ cells than controls. This elevation was not observed in IFN-gamma- or GM-CSF-deficient mice or in those given a high inoculum. Phenotypic analysis revealed that these cells lacked many of the characteristics of natural regulatory T cells, including Foxp3. CD4+CD25+ cells from TNF-alpha-neutralized mice suppressed Ag-specific, but not nonspecific, responses in vitro. Elimination of CD25+ cells in vivo restored protective immunity in mice given mAb to TNF-alpha and adoptive transfer of CD4+CD25+ cells inhibited immunity. In vitro and in vivo, the suppressive effect was reversed by mAb to IL-10. Thus, neutralization of TNF-alpha is associated with the induction of a population of regulatory T cells that alter protective immunity in an Ag-specific manner to Histoplasma capsulatum.     

Complex requirements for nascent and memory immunity in pulmonary histoplasmosis.

The presence of functional T cells is often required for successful resolution of infections with intracellular pathogens, yet the mechanisms by which they contribute to elimination of the invading pathogen in primary and secondary immunity are only partly understood. We report that increased mortality of naive alpha/beta TCR+ or CD4+ T cell-depleted mice infected with the fungus Histoplasma capsulatum is associated with impairment of IFN-gamma production. Upon secondary infection, mice concomitantly depleted of CD4+ and CD8+ cells exhibit decreased survival beyond day 25 of rechallenge, whereas elimination of either T cell subset or B cell deficiency does not result in accelerated mortality compared with controls. Remarkably, despite a decrease of H. capsulatum CFU in lungs of CD4+ plus CD8+-deficient mice, a progressive increase in spleen CFU is observed. The ability to control fungus growth in lungs is associated with vigorous TNF-alpha, but not IFN-gamma, production by bronchoalveolar lavage cells. In contrast, spleen cells from CD4+ plus CD8+-deficient mice are unable to produce TNF-alpha. Thus, the cellular and molecular requirements for protective immunity vary between primary and secondary infection. Furthermore, in secondary histoplasmosis, a sharp contrast can be drawn between lungs and spleens in their reliance upon T cells to control fungal replication. The opposing activities of these organs can be ascribed in part to differential production of TNF-alpha.     

T-cell immune response to human herpesvirus-6 in healthy adults.

The proliferative response of peripheral blood mononuclear cells (PBMC) from healthy adults to human herpesvirus-6 (HHV-6) was examined. It was found that PBMC from 13 of 14 HHV-6-seropositive adults apparently proliferated in response to stimulation with HHV-6 antigen in contrast to the lack of response of cord blood mononuclear cells. In order to confirm the presence of HHV-6-specific memory T cells in the peripheral blood of healthy adults, we established HHV-6-specific T-cell clones from an HHV-6-seropositive individual. CD4+ T-cell clones generated from HHV-6-stimulated PBMC were found to proliferate upon stimulation with HHV-6 in the presence of autologous antigen-presenting cells, but not in response to herpes simplex virus type 1 antigen or mock-infected control antigen. These results indicate that a T-cell immune response against HHV-6 infection is generally present in healthy adult populations.     

Host age as a determinant of naturally acquired immunity to Plasmodium falciparum

The usual course of infection by Plasmodium falciparum among adults who lack a history of exposure to endemic malaria is fulminant. The infection in adults living with hyper- to holoendemic malaria is chronic and benign. Naturally acquired immunity to falciparum malaria is the basis of this difference. Confusion surrounds an essential question regarding this process: What is its rate of onset? Opinions vary because of disagreement over the relationships between exposure to infection, antigenic polymorphism and naturally acquired immunity. In this review, Kevin Baird discusses these relationships against a backdrop of host age as a determinant of naturally acquired immunity to falciparum malaria.     

Characterization of SIV-specific CD4+ T-helper proliferative responses in macaques immunized with live-attenuated SIV

Analysis of immune responses generated by live-attenuated simian immunodeficiency virus (SIV) strains may provide clues to the mechanisms of protective immunity induced by this approach. We examined SIV-specific T-helper responses in macaques immunized with the live-attenuated SIV strains SIVmac239deltanef and SIVmac239delta3. Optimization of the concentration and duration of antigenic stimulation resulted in the detection of relatively strong SIV-specific proliferative responses, with peak stimulation indices of up to 84. SIV-specific proliferative responses were mediated by CD4+ T cells and were major histocompatibility (MHC) class II restricted. Limiting dilution analysis revealed SIV-specific T-helper precursor frequencies of up to 96 per 10(6) peripheral blood mononuclear cells (PBMC). Intracellular flow-cytometric analysis demonstrated the production of interleukin (IL)-2, interferon (IFN)-gamma, RANTES and macrophage inhibitory protein-1alpha (MIP-1alpha) by T lymphocytes from SIVmac239deltanef-vaccinated animals following SIV p55 stimulation. Induction of strong SIV-specific T-helper responses by live-attenuated SIV vaccines may play a role in their ability to induce protective immunity.     

Monokine production by human T cells; IL-1 alpha production restricted to memory T cells.

The production of cytokines is a key event of inflammation. In this report we demonstrate that normal human T cells are capable to produce IL-1 alpha, IL-6, and TNF-alpha, cytokines formerly considered to be monokines. This production was optimal after stimulation with a combination of anti-CD2, PMA, and anti-CD28. All three cytokines were produced in a bioactive form. Both naive (CD4+CD45RA+) and memory (CD4+CD45RO+) subsets of T cells were shown to produce similar amounts of IL-6 and TNF-alpha. In contrast the production of IL-1 alpha was found to be completely restricted to the CD4+CD45RO+ subset. The finding that T cells are such potent producers of these important mediators of the inflammatory response might be a key observation in the appreciation of the role of T cells in chronic inflammation.     

IgM and IgG but not cytokine secretion is restricted to the CD27+ B lymphocyte subset.

In a recent study we reported that CD27 is expressed on a subpopulation of human B lymphocytes and presented circumstantial phenotypic evidence that CD27 expression may be acquired late during B cell differentiation. Here we present functional data showing that, after in vitro stimulation, CD27+ but not CD27- B cells secrete large amounts of both IgM and IgG. Using double immunofluorescence staining of CD27 and IgD, three functionally different B cell subsets representing distinct stages of B cell differentiation can be isolated: 1) the CD27- IgD+ B cells, which do not secrete appreciable Ig; 2) the CD27+IgD+ B cells, which exclusively secrete IgM; and 3) the CD27+IgD- B cells, which comprise the IgG-producing cells. Furthermore, costimulation of CD27- B cells with low m.w. B cell growth factor, in the presence or in the absence of a CD40 mAb, does not induce these cells to become Ig-secreting cells. Although CD27- B cells hardly secrete Ig of any isotype in response to Staphylococcus aureus+IL-2, these cells proliferate vigorously and express the IL-2R alpha chain (CD25) under these stimulatory conditions. Furthermore, both CD27- and CD27+ B cells are capable of producing similar amounts of IL-6 and TNF-alpha. Taken together, these findings indicate that CD27 is a unique non-Ig surface marker discriminating naive from primed B lymphocytes. Furthermore, the capacity to proliferate and to secrete the B cell differentiation factors IL-6 and TNF-alpha already exists at an early B cell differentiation stage at which the cells lack CD27 expression and are not induced to produce Ig.     

Abrogation of in vitro suppression of human immunodeficiency virus type 1 (HIV-1) replication mediated by CD8+ T lymphocytes of asymptomatic HIV-1 carriers by staphylococcal enterotoxin B and phorbol esters through induction of tumor necrosis factor alpha.

CD8+ T lymphocytes of asymptomatic human immunodeficiency virus type 1 (HIV-1) carriers (AC) suppress HIV-1 replication in vitro. Failure of host defense mechanisms and increased virus proliferation are associated with disease progression. The exact mechanisms inducing these changes at the advanced stage of the disease are still obscure. In this study, we searched for experimental conditions favoring the abrogation of the suppression of viral replication in peripheral blood mononuclear cells (PBMC) of AC by using various pharmacological and biological probes modifying cell activation. Among such agents, staphylococcal enterotoxin B (SEB) and phorbol 12-myristate 13-acetate (PMA) markedly increased otherwise low levels of HIV-1 replication in cultures of phytohemagglutinin-stimulated AC PBMC following in vitro HIV-1 LAI infection. A similar but less pronounced virus induction was also observed in macrophage-tropic HIV-1. Individual pretreatment of CD4+ and CD8+ PBMC fractions with these agents caused a reduction in CD8+ cell proliferation and enhanced HIV-1 replication in CD4+ cells. SEB- and PMA-mediated augmentation of HIV-1 replication in AC PBMC was significantly blocked by neutralizing antibody to tumor necrosis factor-alpha (TNF-alpha), although recombinant TNF-alpha alone failed to reproduce the effects of SEB or PMA. Our results suggest that the induction of TNF-alpha may be one of the mechanisms that overcomes the CD8+-induced suppression of HIV-1 replication in AC and that it may induce HIV-1 replication.