scholarly journals CD8+ T Cells Implicated in the Pathogenesis of Allergic Fungal Rhinosinusitis

2014 ◽  
Vol 5 (3) ◽  
pp. ar.2014.5.0103 ◽  
Author(s):  
Harshita Pant ◽  
Peta Macardle
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Division ◽  
T Cell ◽  
T Cell Response ◽  
T Cell Subsets ◽  
T Cell Proliferation ◽  
Fungal Rhinosinusitis ◽  
Allergic Fungal Rhinosinusitis ◽  
Fungal Allergy

Fungi in paranasal sinuses are characteristic and considered a major pathogenic factor in a subset of chronic rhinosinusitis (CRS) patients, known as allergic fungal rhinosinusitis (AFRS). CD8+ T cells are enriched in AFRS sinuses but their role in fungal-specific responses is unknown. Alternaria alternata– and Aspergillus fumigatus–specific T lymphocyte responses were investigated in 6 AFRS patients, 10 eosinophilic mucus CRS (EMCRS) patients, 10 CRS with nasal polyps (CRSwNPs) patients, 6 allergic rhinitis with fungal allergy (ARFA) patients, and five controls. Fungal-specific proliferation of human peripheral blood mononuclear cells (PBMCs) was studied prospectively. Proliferating cells were examined for CD3, CD4, CD8, and CD25 expression. Relevant clinical characteristics, fungal allergy, detection of fungi in sinuses, and CD4+ and CD8+ composition of sinus T cells were also examined. CD4+ T-cell division to fungi occurred in all samples, regardless of fungal allergy or CRS. Fungal-specific CD8+ T-cell division occurred in all ARFA and control samples and the majority of CRSwNP patients; however, CD8+ T cells failed to proliferate in AFRS and EMCRS patients. The CD8+ T cells from AFRS patients also did not up-regulate the activation marker, CD25, with fungal antigen exposure. Presence of A. alternata– and A. fumigatus–specific CD4+ and CD8+ T-cell proliferation in healthy individuals, ARFA, and CRSwNP patients suggests that both T-cell subsets may be important in immune responses to these fungi. In AFRS and EMCRS patients, only fungal-specific CD4+ T-cell proliferation occurred; hence, a lack of CD8+ T-cell proliferation and activation in the presence of sinus eosinophilic mucus in these patients, regardless of fungal allergy, is a novel finding. This raises the question whether a dysfunctional CD8+ T-cell response predisposes to ineffective clearance and accumulation of fungi in the sinuses of susceptible patients.

Cord Blood Nucleated Cells Induce Delayed Proliferative and Cytotoxic T Cell Alloreactivity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5138-5138
Author(s):  
Dolores Mahmud ◽  
Sandeep Chunduri ◽  
Javaneh Abbasian ◽  
John Maciejewski ◽  
Ronak Iqbal ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Cell Proliferation ◽  
Cd34 Cells ◽  
Ctl Activity

Abstract Transplantation of HLA-mismatched nucleated cells from cord blood (CB) has reduced risks of graft rejection and severe acute graft-versus-host disease. In this study we analyzed the in-vitro alloantigen presenting capacity of cord blood nucleated cells. CB mononuclear cells (MNCs) or immunomagnetically-selected CD34+ cells, or CD14+ monocytes, were irradiated and tested as stimulators of allogeneic blood T cells in primary (stimulator:responder ratio = 1:1) or secondary (stimulator:responder ratio = 1:2) mixed leukocyte culture (MLC), or in cytotoxic T-lymphocytes (CTL) assays. CB-MNCs failed to induce allogeneic T cell proliferation in 6-days primary MLC, whereas CD34+ or CD14+ cells stimulated brisk T cell responses. A suppressive effect of CB-MNCs was ruled out since CD3+ cell-depletion of CB-MNCs did not restore CB immunogenicity and the addition of increasing doses of CB-MNCs did not inhibit T cell alloreactivity to CD34+ cells. Despite allogeneic T cells were unresponsive to CB-MNCs after primary and secondary MLC, T cell anergy was ruled out since T cells that were unresponsive after primary MLC proliferated potently in secondary MLC stimulated with CB CD34+ cells, and even more with CB monocyte-derived dendritic cells (Mo-DC) generated in-vitro with GM-CSF and IL-4. Interestingly, after co-culture with irradiated allogeneic T cells for 6 days, CB-MNCs showed a greater proportion of CD86+ cells and elicited allo- T cell proliferation. In addition, allo-CTL activity was induced by CB-MNCs only after restimulating effector cells for 3–4 weeks (26±7% lysis of antigen-specific PHA-blast at 50:1 E:T ratio), and was comparable to CTL activity induced after 1 week by Mo-DC generated from the same CB. When T cell effectors were stimulated by combining two incompatible cord blood MNCs mixed together, CTL activity was then detected after 4 weeks against both of them regardless of the CB:CB cell ratio. These results show an impaired allo-APC activity of CB-MNCs, without suppressive or tolerogenic activity. These findings might partially explain the initial engraftment of combined HLA mismatched CB grafts in vivo, however they also suggest that a delayed T cell response may occur due to CB-derived APCs activating CTLs.

scholarly journals Naive CD8+ T cells differentiate into protective memory-like cells after IL-2–anti–IL-2 complex treatment in vivo

2007 ◽  
Vol 204 (8) ◽  
pp. 1803-1812 ◽  
Author(s):  
Daisuke Kamimura ◽  
Michael J. Bevan
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Memory Phenotype

An optimal CD8+ T cell response requires signals from the T cell receptor (TCR), co-stimulatory molecules, and cytokines. In most cases, the relative contribution of these signals to CD8+ T cell proliferation, accumulation, effector function, and differentiation to memory is unknown. Recent work (Boyman, O., M. Kovar, M.P. Rubinstein, C.D. Surh, and J. Sprent. 2006. Science. 311:1924–1927; Kamimura, D., Y. Sawa, M. Sato, E. Agung, T. Hirano, and M. Murakami. 2006. J. Immunol. 177:306–314) has shown that anti–interleukin (IL) 2 monoclonal antibodies that are neutralizing in vitro enhance the potency of IL-2 in vivo. We investigated the role of IL-2 signals in driving CD8+ T cell proliferation in the absence of TCR stimulation by foreign antigen. IL-2 signals induced rapid activation of signal transducer and activator of transcription 5 in all CD8+ T cells, both naive and memory phenotype, and promoted the differentiation of naive CD8+ T cells into effector cells. IL-2–anti–IL-2 complexes induced proliferation of naive CD8+ T cells in an environment with limited access to self–major histocompatibility complex (MHC) and when competition for self-MHC ligands was severe. After transfer into wild-type animals, IL-2–activated CD8+ T cells attained and maintained a central memory phenotype and protected against lethal bacterial infection. IL-2–anti–IL-2 complex–driven memory-like CD8+ T cells had incomplete cellular fitness compared with antigen-driven memory cells regarding homeostatic turnover and cytokine production. These results suggest that intense IL-2 signals, with limited contribution from the TCR, program the differentiation of protective memory-like CD8+ cells but are insufficient to guarantee overall cellular fitness.

Disruption of T Cell Suppression in Chronic Lymphocytic Leukemia by CD200 Blockade.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2072-2072
Author(s):  
Christian P Pallasch ◽  
Susanne Ulbrich ◽  
Reinhild Brinker ◽  
Robert A Uger ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
In Vitro Culture ◽  
Mixed Lymphocyte Reaction ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Therapeutic Benefits

Abstract Suppression of patients’ T-cells is a key event in CLL pathogenesis and was demonstrated to be mediated by direct cell-cell contact of malignant CLL cells with T-cells. CD200 plays a critical role in regulating the immune system and has been shown to be up-regulated on the surface of different tumors including CLL. In this study we addressed the effects of CD200 over-expression on CLL cells on autologous T cells in a mixed lymphocyte reaction system. We used native and CD40 ligand (CD40L)- stimulated CLL cells as antigen-presenting cells (APCs) to expand autologous T cells of 14 patients. T-cell proliferation was analyzed over 3 weeks of in vitro culture. A functional anti- CD200 antibody (1B9) was added to reveal CD200-mediated immunosuppression in the autologous system. Expansion of patient T-cells was assessed by flow cytometry including intracellular staining of FOXP3. Specificity towards CLL-specific antigens was monitored applying fibromodulin derived peptides for detection of specific T-cells by ELISPOT analysis. T-cell proliferation over 3 weeks of in vitro culture was significantly enhanced compared to control cells when using CD40L-stimulated APCs and an anti-CD200 antibody (p=0.0004). CD200 blockade was further shown to stimulate antigen-specific T-cell responses towards the F2 and F4 peptides of the CLL-associated antigen fibromodulin (p=0.04). Finally, the number of CD4+/CD25high/FOXP3+ T cells (Treg) was significantly decreased in CD200 treated mixed lymphocyte reaction (p=0.04). In summary, CD200 blockade may provide therapeutic benefits in CLL by enhancing T-cell expansion, augmenting an antigen-specific T cell response with suppression of regulatory T cells. CD200 seems to be an important immunosuppressive molecule in CLL: by CD200 blockade immune suppression can be overcome by altering tolerance to tumor antigens and deregulation of regulatory T cells. This combination of an immune induction paralleled by a disruption of immunosuppressive factors makes anti-CD200 mAb a powerful tool for future treatment of CLL, possibly in combination with other B cell cytotoxic or immunostimulatory approaches.

Transregulation of memory CD8 T-cell proliferation by IL-15Rα+ bone marrow–derived cells

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 988-994 ◽  
Author(s):  
Kimberly S. Schluns ◽  
Kimberly D. Klonowski ◽  
Leo Lefrançois
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
T Cells ◽  
Cell Division ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Proliferation ◽  
Memory Cd8 T Cells ◽  
Basal Proliferation

AbstractInterleukin 15 (IL-15) and the IL-15 receptor α (IL-15Rα) chain are both required for the basal proliferation of memory CD8 T cells, but which cell types are required to express IL-15 or IL-15Rα to mediate this proliferation is not known. Using bone marrow (BM) chimeras, we showed that virus-specific CD8 memory T-cell proliferation was driven by IL-15 produced by either BM-derived or parenchymal cells. Experiments using mixed BM chimeras showed that IL-15Rα expression by memory CD8 T cells was not required for their division. In addition, wild-type memory CD8 T cells did not divide after transfer into IL-15Rα-/- mice. Further analyses demonstrated that IL-15Rα+ BM-derived cells were crucial in driving memory CD8 T-cell division in the spleen while both parenchymal and BM-derived cells promoted memory cell division in the lung. Proliferation in response to soluble IL-15 in vivo required expression of IL-15Rα by opposing cells and IL-15Rβ by CD8 memory cells, indicating that IL-15 interacted directly with the T cells. These results indicate that transpresentation of IL-15 by IL-15Rα on BM-derived cells mediates the basal proliferation of memory CD8 T cells. (Blood. 2004;103:988-994)

scholarly journals Effects of pregnancy-specific β-1-glycoprotein on the helper T-cell response

2019 ◽  
Vol 71 (2) ◽  
pp. 369-378 ◽  
Author(s):  
Valeria Timganova ◽  
Maria Bochkova ◽  
Pavel Khramtsov ◽  
Sofia Kochurova ◽  
Mikhail Rayev ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Suppressive Effect ◽  
T Cell Response ◽  
Effector Memory ◽  
T Cell Proliferation ◽  
Helper T Cell ◽  
Innate And Adaptive Immunity

Pregnancy-specific ?-1-glycoproteins (PSGs) are capable of regulating innate and adaptive immunity. As fetal antigens circulate in the blood of pregnant women, it is of particular interest to reveal the effects of PSGs on the differentiation of memory T cells in the context of maternal-fetal tolerance formation. We studied if, native PSG preparation affects helper T-cell proliferation, the frequencies of CD4+CD45R0+, CD4+CD45RA+, CD4+CD45RA+CD45R0+cells, naive CD45RA+CD45R0-CD62L+ cells (NAIVE), central memory CD45RA-CD45R0+CD62L+ cells (TCM), effector memory helper T cells (CD45RA-CD45R0+CD62L- (TEM) and CD45RA+CD45R0-CD62L- cells (TEMRA), together with IL-4 and IFN-? production by all ?D4+ T cells. The suppressive effect of PSG on helper T-cell proliferation was established. It was found that PSG does not influence the frequencies of CD45RA+ and CD45R0+ cells, while it decreased the percentage of CD45RA+CD45R0+ cells. PSG increased the percentage of NAIVE cells in culture, and prevented the conversion of these cells into TEMRA, without affecting the levels of TCM and TEM. In addition, PSG lowered the amount of IL-4 and IFN-? in the supernatants of helper T-cell cultures. As TEMRA exhibit cytotoxic activity that is unfavorable during pregnancy, the revealed PSG effects may play a fetoprotective role in vivo.

scholarly journals Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hongda Wang ◽  
Yiming Zhao ◽  
Bingbing Ren ◽  
Yafei Qin ◽  
Guangming Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Liver Function ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Endometrial Regenerative Cells ◽  
Regenerative Cells

Abstract Background Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. Methods ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. Results After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. Conclusions The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.

scholarly journals CD2 regulates responsiveness of activated T cells to interleukin 12.

1995 ◽  
Vol 182 (3) ◽  
pp. 721-731 ◽  
Author(s):  
J A Gollob ◽  
J Li ◽  
E L Reinherz ◽  
J Ritz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Interleukin 12 ◽  
Activated T Cells ◽  
Functional Link ◽  
Ifn Gamma ◽  
Helper Cell Type

Interleukin (IL) 12 is a 70-kD heterodimeric cytokine produced by antigen-presenting cells (APCs) such as macrophages in response to infectious pathogens and interferon (IFN) gamma. The varied immunomodulatory effects of IL-12 include the stimulation of proliferation and IFN-gamma production by T cells, and it also has a central role in the development of the T helper cell type 1 immune phenotype. We undertook the production of antibodies capable of modulating the response of T cells to IL-12, and in the process we discovered two antibodies that inhibited the ability of IL-12 to stimulate T cell proliferation. In this report, we demonstrate that these anti-bodies recognize CD2, and we show how antibodies directed toward either the adhesion domain of CD2 or its ligand, CD58, specifically inhibit IL-12 induced proliferation and IFN-gamma production by phytohemagglutinin-activated T cells, leaving the response to IL-12 unaffected. A three-to fourfold reduction in proliferation and IFN-gamma production was observed at IL-12 concentrations as high as 1 nM, with complete inhibition occurring at < or = 1 pM. This novel effect is not directly mediated at the level of the IL-12 receptor, as shown by the inability of these antibodies to block IL-12 binding to activated T cells. Furthermore, by using activating pairs of CD2 antibodies, we show that CD2 stimulation strongly synergizes with IL-12, even at 0.1 pM, in inducing both T cell proliferation and IFN-gamma production. Cytolytic T lymphocyte-associated antigen 4-immunoglobulin-mediated inhibition of the B7/CD28 interaction did not affect the T cell response to either IL-12 or IL-2, but the removal of APCs selectively diminished the proliferative response to IL-12. Based on this data, we hypothesize that CD2 has a central role in an IL-12/IFN-gamma positive feedback loop between T cell and APC, providing the key functional link via a CD2/CD58 interaction that controls T cell responsiveness to IL-12. This model provides a basis for future investigations aimed at defining the signaling mechanisms that mediate this cytokine-specific regulatory effect of CD2, and it offers insight into how a cytokine receptor and distinct adhesion molecule can interact to modulate responsiveness to that cytokine. In addition, it underscores the possibility that the clinical potential of an immunomodulatory drug like IL-12 may be governed by the presence or absence of specific costimulation.

scholarly journals Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.

1992 ◽  
Vol 176 (6) ◽  
pp. 1595-1604 ◽  
Author(s):  
P S Linsley ◽  
J L Greene ◽  
P Tan ◽  
J Bradshaw ◽  
J A Ledbetter ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Subsets ◽  
T Cell Proliferation ◽  
Activated T Cells ◽  
Activated T Lymphocytes ◽  
T Cell Adhesion

T cell costimulation by molecules on the antigen presenting cell (APC) is required for optimal T cell proliferation. The B7 molecule on APC binds the T lymphocyte receptor CD28, triggering increased interleukin 2 (IL-2) production and subsequent T cell proliferation. CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown. Here we have developed monoclonal antibodies (mAbs) specific for CTLA-4 and have investigated these questions. mAbs were produced that bound CTLA-4 but not CD28, and that blocked binding of CTLA-4 to B7. CTLA-4 expression as measured by these mAbs was virtually undetectable on resting T cells, but was increased several hundred-fold during T cell activation. On activated lymphocytes, CTLA-4 was expressed equally on CD4+ and CD8+ T cell subsets and was coexpressed with CD25, CD28, and CD45RO. CTLA-4 expression was lower than that of CD28, reaching a maximum of approximately 1/30-50 the level of CD28. Despite its lower expression, CTLA-4 was responsible for much of the B7 binding by large activated T cells. Anti-CTLA-4 mAb 11D4 and anti-CD28 mAb 9.3 acted cooperatively to inhibit T cell adhesion to B7, and to block T cell proliferation in primary mixed lymphocyte culture. When coimmobilized with anti T cell receptor (TCR) mAb, anti-CTLA-4 mAbs were less effective than anti-CD28 mAb 9.3 at costimulating proliferation of resting or activated T cells. However, coimmobilized combinations of anti-CD28 and anti-CTLA-4 were synergistic in their ability to augment anti-TCR-induced proliferation of preactivated CD4+ T cells. These results indicate that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7.

scholarly journals Inhibition of Allogeneic and Autologous T Cell Proliferation by Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Ewa Kuca-Warnawin ◽  
Magdalena Plebańczyk ◽  
Krzysztof Bonek ◽  
Ewa Kontny
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Ankylosing Spondylitis ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Response ◽  
T Cell Proliferation

Background. In ankylosing spondylitis (AS), accompanied by chronic inflammation, T cell expansion plays a pathogenic role; the immunoregulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) are impaired, while functional characteristics of their adipose tissue-derived counterparts are (ASCs) unknown. Methods. We evaluated the antiproliferative activity of AS/ASCs, obtained from 20 patients, towards allogeneic and autologous T lymphocytes, using ASCs from healthy donors (HD/ASCs) as the reference cell lines. The PHA-activated peripheral blood mononuclear cells (PBMCs) were cocultured in cell-cell contact and transwell conditions with untreated or TNF + IFNγ- (TI-) licensed ASCs, then analyzed by flow cytometry to identify proliferating and nonproliferating CD4+ and CD8+ T cells. The concentrations of kynurenines, prostaglandin E2 (PGE2), and IL-10 were measured in culture supernatants. Results. In an allogeneic system, HD/ASCs and AS/ASCs similarly decreased the proliferation of CD4+ and CD8+ T cells and acted mainly via soluble factors. The concentrations of kynurenines and PGE2 inversely correlated with T cell proliferation, and selective inhibitors of these factors synthesis significantly restored T cell response. AS/ASCs exerted a similar antiproliferative impact also on autologous T cells. Conclusion. We report for the first time that despite chronic in vivo exposure to inflammatory conditions, AS/ASCs retain the normal capability to restrain expansion of allogeneic and autologous CD4+ and CD8+ T cells, act primarily via kynurenines and PGE2, and thus may have potential therapeutic value. Some distinctions between the antiproliferative effects of AS/ASCs and HD/ASCs suggest in vivo licensing of AS/ASCs.

scholarly journals Defective Human Immunodeficiency Virus-Specific CD8+ T-Cell Polyfunctionality, Proliferation, and Cytotoxicity Are Not Restored by Antiretroviral Therapy

2009 ◽  
Vol 83 (22) ◽  
pp. 11876-11889 ◽  
Author(s):  
Stephen A. Migueles ◽  
Kristin A. Weeks ◽  
Eric Nou ◽  
Amy M. Berkley ◽  
Julia E. Rood ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Proliferating Cells ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Rna Levels

ABSTRACT Identifying the functions of human immunodeficiency virus (HIV)-specific CD8+ T cells that are not merely modulated by the level of virus but clearly distinguish patients with immune control from those without such control is of paramount importance. Features of the HIV-specific CD8+ T-cell response in antiretroviral-treated patients (designated Rx <50) and untreated patients (long-term nonprogressors [LTNP]) matched for very low HIV RNA levels were comprehensively examined. The proliferative capacity of HIV-specific CD8+ T cells was not restored in Rx <50 to the level observed in LTNP, even though HIV-specific CD4+ T-cell proliferation in the two patient groups was comparable. This diminished HIV-specific CD8+ T-cell proliferation in Rx <50 was primarily due to a smaller fraction of antigen-specific cells recruited to divide and not to the numbers of divisions that proliferating cells had undergone. Exogenous interleukin-2 (IL-2) induced proliferating cells to divide further but did not rescue the majority of antigen-specific cells with defective proliferation. In addition, differences in HIV-specific CD8+ T-cell proliferation could not be attributed to differences in cellular subsets bearing a memory phenotype, IL-2 production, or PD-1 expression. Although polyfunctionality of HIV-specific CD8+ T cells in Rx <50 was not restored to the levels observed in LTNP despite prolonged suppression of HIV RNA levels, per-cell cytotoxic capacity was the functional feature that most clearly distinguished the cells of LTNP from those of Rx <50. Taken together, these data suggest that there are selective qualitative abnormalities within the HIV-specific CD8+ T-cell compartment that persist under conditions of low levels of antigen.

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