scholarly journals Anti-Asialo GM1 treatment during secondaryToxoplasma gondiiinfection is lethal and depletes T cells

2019 ◽  
Author(s):  
Daria L. Ivanova ◽  
Steve L. Denton ◽  
Jason P. Gigley
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Secondary Infection ◽  
Parasite Burden ◽  
Effector Memory

AbstractUsing vaccine challenge model ofT. gondiiinfection, we found that treatments with two commonly used for NK cell depletion antibodies resulted in different survival outcomes during secondary infection. Anti-ASGM1 resulted in 100% death and greater parasite burden at the site of infection than anti-NK1.1. Anti-NK1.1 treatment resulted in increased parasite burdens, but animals did not die. Further we found that anti-ASGM1 treatment depleted T cells. CD8+ T cells were more susceptible that CD4+ T cells to the treatment. ASGM1 was expressed on a higher percentage of CD8+ T cells than CD4+ T cells and CD8+ T cells. InT. gondii-immunized animals ASGM1 was enriched on effector memory (Tem) and central memory (Tcm) CD8+ T cells. However, Tem were more susceptible to the treatment. After secondary infection, Tem, Tcm, effector (Tef) and naïve (Tn) CD8+ T cells were positive for ASGM1. Anti-ASGM1 treatment during reinfection resulted in greater depletion of activated IFNγ+, Granzyme B+, Tem and Tef than Tcm and Tn CD8+ T cells. Anti-ASGM1 also depleted IFNγ+ CD4+ T cells. Recombinant IFNγ supplementation prolonged survival of anti-ASGM1 treated mice, demonstrating that this antibody eliminated IFNγ-producing T and NK cells important for control of the parasite. These results highlight that anti-ASGM1 antibody is not an optimal choice for targeting only NK cells and more precise approaches should be used. This study uncovers ASGM1 as a marker of activated effector T cells and the potential importance of changes in sialylation in lipid rafts for T cell activation duringT. gondiiinfection.

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

Anti-GvHD Effect of Antithymocyte Globulin Is Mediated by Antibodies Binding to T Cells and Regulatory NK Cells, and Less So or Not at All by Antibodies Binding to Other Mononuclear Cell Subsets

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2346-2346
Author(s):  
Mette Hoegh-Petersen ◽  
Minaa Amin ◽  
Yiping Liu ◽  
Alejandra Ugarte-Torres ◽  
Tyler S Williamson ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Antithymocyte Globulin ◽  
Chronic Gvhd ◽  
Wilcoxon Test ◽  
Effector Memory

Abstract Abstract 2346 Introduction: Polyclonal rabbit-anti-human T cell globulin may decrease the likelihood of graft-vs-host disease (GVHD) without increasing the likelihood of relapse. We have recently shown that high levels of antithymocyte globulin (ATG) capable of binding to total lymphocytes are associated with a low likelihood of acute GVHD grade 2–4 (aGVHD) as well as chronic GVHD needing systemic therapy (cGVHD) but not increased likelihood of relapse (Podgorny PJ et al, BBMT 16:915, 2010). ATG is polyclonal, composed of antibodies for antigens expressed on multiple cell subsets, including T cells, B cells, NK cells, monocytes and dendritic cells. These cell subsets may play a role in the pathogenesis of GVHD. The anti-GVHD effect of ATG may be mediated through killing/inhibition of one or several of these cell subsets (eg, T cells) or their subsets (eg, naïve T cells as based on mouse experiments naïve T cells are thought to play a major role in the pathogenesis of GVHD). To better understand the mechanism of action of ATG on GVHD, we set out to determine levels of which ATG fraction (capable of binding to which cell subset) are associated with subsequent development of GVHD. Patients and Methods: A total of 121 patients were studied, whose myeloablative conditioning included 4.5 mg/kg ATG (Thymoglobulin). Serum was collected on day 7. Using flow cytometry, levels of the following ATG fractions were determined: capable of binding to 1. naïve B cells, 2. memory B cells, 3. naïve CD4 T cells, 4. central memory (CM) CD4 T cells, 5. effector memory (EM) CD4 T cells, 6. naïve CD8 T cells, 7. CM CD8 T cells, 8. EM CD8 T cells not expressing CD45RA (EMRA-), 9. EM CD8 T cells expressing CD45RA (EMRA+), 10. cytolytic (CD16+CD56+) NK cells, 11. regulatory (CD16-CD56high) NK cells, 12. CD16+CD56− NK cells, 13. monocytes and 14. dendritic cells/dendritic cell precursors (DCs). For each ATG fraction, levels in patients with versus without aGVHD or cGVHD were compared using Mann-Whitney-Wilcoxon test. For each fraction for which the levels appeared to be significantly different (p<0.05), we determined whether patients with high fraction level had a significantly lower likelihood of aGVHD or cGVHD than patients with low fraction level (high/low cutoff level was determined from ROC curve, using the point with maximum sum of sensitivity and specificity). This was done using log-binomial regression models, ie, multivariate analysis adjusting for recipient age (continuous), stem cell source (marrow or cord blood versus blood stem cells), donor type (HLA-matched sibling versus other), donor/recipient sex (M/M versus other) and days of follow up (continuous). Results: In univariate analyses, patients developing aGVHD had significantly lower levels of the following ATG fractions: binding to naïve CD4 T cells, EM CD4 T cells, naïve CD8 T cells and regulatory NK cells. Patients developing cGVHD had significantly lower levels of the following ATG fractions: capable of binding to naïve CD4 T cells, CM CD4 T cells, EM CD4 T cells, naïve CD8 T cells and regulatory NK cells. Patients who did vs did not develop relapse had similar levels of all ATG fractions. In multivariate analyses, high levels of the following ATG fractions were significantly associated with a low likelihood of aGVHD: capable of binding to naïve CD4 T cells (relative risk=.33, p=.001), EM CD4 T cells (RR=.30, p<.001), naïve CD8 T cells (RR=.33, p=.002) and regulatory NK cells (RR=.36, p=.001). High levels of the following ATG fractions were significantly associated with a low likelihood of cGVHD: capable of binding to naïve CD4 T cells (RR=.59, p=.028), CM CD4 T cells (RR=.49, p=.009), EM CD4 T cells (RR=.51, p=.006), naïve CD8 T cells (RR=.46, p=.005) and regulatory NK cells (RR=.55, p=.036). Conclusion: For both aGVHD and cGVHD, the anti-GVHD effect with relapse-neutral effect of ATG appears to be mediated by antibodies to antigens expressed on naïve T cells (both CD4 and CD8), EM CD4 T cells and regulatory NK cells, and to a lesser degree or not at all by antibodies binding to antigens expressed on B cells, cytolytic NK cells, monocytes or DCs. This is the first step towards identifying the antibody(ies) within ATG important for the anti-GVHD effect without impacting relapse. If such antibody(ies) is (are) found in the future, it should be explored whether such antibody(ies) alone or ATG enriched for such antibody(ies) could further decrease GVHD without impacting relapse. Disclosures: No relevant conflicts of interest to declare.

New Insights into the Mechanism of Action (MoA) of First-in-Class IgG-Based Bcma T-Cell Bispecific Antibody (TCB) for the Treatment of Multiple Myeloma (MM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2096-2096 ◽  
Author(s):  
Laura Moreno ◽  
Aintzane Zabaleta ◽  
Diego Alignani ◽  
Marta Lasa ◽  
Patricia Maiso ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Cell Activation ◽  
Rational Combination ◽  
Dose Dependent ◽  
Tumor Cell Lysis

Abstract Novel agents have improved outcomes in MM, but prognosis after patients relapse remains poor and new drugs with novel MoA are needed. The breakthrough of immuno-oncology has rendered new therapeutic options, and most recently we reported on EM801, a novel BCMA-TCB that showed remarkably efficacy when used as single agent in primary bone marrow (BM) samples from MM patients (Seckinger, Blood 2015;126: abstr 117). Because of its novelty, further knowledge about the MoA of BCMA-TCB is of utmost importance to improve its efficacy by designing rational treatment combinations. In order to optimize the in vitro efficacy of the BCMA-TCB, we started by investigating in primary BM samples from 6 MM patients whether longer treatment periods with BCMA-TCB2 (a BCMA-TCB candidate sharing similar "2+1" structure of EM801 but displaying higher affinity to BCMA) would increase MM cell death. Upon treating samples with BCMA-TCB2 for 48h vs 96h, we noted a 2-fold increment in MM tumor cell lysis at 1nM and 10nM concentrations (Panel A). In parallel, the phenotypic profiles of CD4 and CD8 T cells showed that BCMA-TCB2 induced robust activation (ie. dose-dependent increment in CD69, CD25, HLADR after exposure to 100pM, 1nM and 10nM of BCMA-TCB2), but also led to the natural emergence of the checkpoint inhibitor PD-1 in the surface of activated CD4 and CD8 T cells (Panel B). We then investigated if there was a correlation between the percentage of PD-1 positive CD4 and CD8 T cells and the efficacy of BCMA-TCB2; interestingly, those patients with lower frequencies of PD-1 positive CD4 and CD8 T cells prior to treatment showed the highest rates of MM tumor cell lysis after 48h and 96h of BCMA-TCB2 at 10nM of (r=0.6, P=0.04; Panel C). By contrast, upon measuring the concentration of soluble BCMA and APRIL in the supernatants of primary BM samples from 16 MM patients treated with BCMA-TCB, we found no significant differences between responding (n=11) and non-responding (n=5) patients. Similar results were observed upon comparing the density of BCMA in the surface of MM tumor cells from responding vs non-responding patients (1256 vs 1522 SABC units; P=87). Since the efficacy of BCMA-TCB2 was found to be intrinsically related to the phenotype and activation status of T cells, we then investigated whether we could further harness immune cells by combining BCMA-TCB2 with three drugs representing different types of immunotherapy: lenalidomide (IMIDs), anti-PD1 (checkpoint inhibitors) and daratumumab (mAb). H929 MM cells were co-cultured with human leukocytes (n=5) and challenged to suboptimal concentrations of BCMA-TCB2 (10pM) alone, or in combination with standard doses of lenalidomide (1µM), anti-PD1 (10µg/ml) and daratumumab (10µg/ml) (Panel D). Interestingly, we observed that combining BCMA-TCB2 with lenalidomide or daratumumab significantly increased their anti-MM efficacy by 4-fold and 2.5-fold, respectively. Because lenalidomide and daratumumab share in common that they rely, at least in part, on activated NK cells to eradicate MM cells, we hypothesized whether such robust T cell activation induced by BCMA-TCB2 was leading to co-stimulation of NK cells. First, we demonstrated by analyzing the transcriptomes of T cells prior and after treatment exposure (n=3), that BCMA-TCB2 modulated the transcriptomes of CD4 and CD8 T cells (159 and 141 deregulated genes, respectively), consistent with enhanced activation and T-cell mediated inflammatory response (eg. TNFRS18, STAT1, CCL4). Furthermore, we observed a dose-dependent and significant increment of the CD69 (2-fold), CD25 (2.5-fold) and HLADR (4-fold) activation markers in the surface of NK cells from primary BM samples of 11 MM patients treated with BCMA-TCB2 (Panel E), suggesting a functional crosstalk between activated T cells and NK cells. In conclusion, we showed that the promising pre-clinical activity of the first-in-class IgG-based BCMA-TCB can be further enhanced by longer treatment periods followed by robust T cell activation. The observation that the efficacy of BCMA-TCB is intrinsically related to the activation status of T cells suggests its rational combination with IMIDs as demonstrated here. Most interestingly, potential crosstalk between activated T and NK cells could lead to enhanced function of the later immune subset, and provide a rational combination between BCMA-TCB and anti-CD38 antibodies to eradicate MM cells through highly activated T and NK cells. Figure Figure. Disclosures Strein: EngMab: Employment. Vu:EngMab: Employment. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

scholarly journals c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Have Distinct Roles in CD8+ T Cell Activation

2002 ◽  
Vol 195 (7) ◽  
pp. 811-823 ◽  
Author(s):  
Dietrich Conze ◽  
Troy Krahl ◽  
Norman Kennedy ◽  
Linda Weiss ◽  
Joanne Lumsden ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Surface Expression ◽  
Chain Gene ◽  
Α Chain

The c-Jun NH2-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8+ T cells. Unlike CD4+ T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8+ T cells. In contrast, JNK1-deficient CD8+ T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor α chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8+ T cells can account for the impaired IL-2 receptor α chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8+ T cell activation and these roles differ from those in CD4+ T cells.

Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Blood ◽  
2021 ◽  
Author(s):  
Melissa M Berrien-Elliott ◽  
Michelle Becker-Hapak ◽  
Amanda F. Cashen ◽  
Miriam T. Jacobs ◽  
Pamela Wong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Clinical Activity ◽  
Allogeneic Cell

NK cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from two independent clinical trial cohorts treated with MHC-haploidentical NK cell therapy for relapsed/refractory AML revealed that cytokine support by systemic IL-15 (N-803) resulted in reduced clinical activity, compared to IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T cell numbers in patients treated with IL-15/N-803, compared to IL2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T cell activation and proliferation, compared to IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived ML NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15.

scholarly journals Novel APC-like properties of human NK cells directly regulate T cell activation

2015 ◽  
Author(s):  
Jacob Hanna ◽  
Ofer Mandelboim
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
Antigen Uptake

Initiation of the adaptive immune response is dependent on the priming of naive T cells by APCs. Proteomic analysis of unactivated and activated human NK cell membrane-enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since they upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules. Furthermore, by manipulating antigen administration, we show that NK cells possess multiple independent unique pathways for antigen uptake. These results highlight NK cell-mediated cytotoxicity and specific ligand recognition by cell surface-activating receptors on NK cells as unique mechanisms for antigen capturing and presentation. In addition, we analyzed the T cell-activating potential of human NK cells derived from different clinical conditions, such as inflamed tonsils and noninfected and CMV-infected uterine decidual samples, and from transporter-associated processing antigen 2–deficient patients. This in vivo analysis revealed that proinflammatory, but not immune-suppressive, microenvironmental requirements can selectively dictate upregulation of T cell-activating molecules on NK cells. Taken together, these observations offer new and unexpected insights into the direct interactions between NK and T cells and suggest novel APC-like activating functions for human NK cells.

scholarly journals CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3818-3823 ◽  
Author(s):  
Luca Gattinoni ◽  
Anju Ranganathan ◽  
Deborah R. Surman ◽  
Douglas C. Palmer ◽  
Paul A. Antony ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Peripheral Tolerance ◽  
The Impact

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8+ T cells by using the glycoprotein (gp) 100–specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4–/– mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8+ T-cell population and large numbers of CD4+ T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4–/– CD8+ T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4–mediated inhibition on CD8+ T cells did not directly promote enhancement of their effector functions. Removal of CD4+ T cells by crossing the pmel-1 CLTA-4–/– mouse onto a Rag-1–/– background resulted in the complete abrogation of CD8+ T-cell activation and autoimmune manifestations. The effects of CD4+ CLTA-4–/– T cells were dependent on the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4–/– T-cell–mediated autoimmunity and tumor immunity required CD4+ T cells in which the function was dysregulated by the absence of CTLA-4–mediated negative costimulation.

scholarly journals NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1342-1351 ◽  
Author(s):  
Zusen Fan ◽  
Ping Yu ◽  
Yang Wang ◽  
Yugang Wang ◽  
May Lynne Fu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Dependent Manner ◽  
Cd8 Cells ◽  
Ifn Γ

Natural killer (NK) cells are generally reported as innate effector cells for killing virally infected and transformed cells. It is unclear how NK cells evoke adaptive immunity to eradicate tumors. We now demonstrate that the TNF superfamily member, LIGHT, known as TNFSF14 and a T-cell costimulatory molecule, is a critical ligand for the activation of NK cells. Herpesvirus entry mediator (HVEM) is expressed on NK cells, and its engagement with LIGHT mediates NK-cell activation. The expression of LIGHT inside tumors leads to rapid rejection in a NK-dependent manner. Both NK and CD8+ cells are essential but not sufficient for the rejection of tumors because mice lacking either population fail to reject the tumor. Interestingly, activated NK cells do not kill tumors directly but can facilitate the priming of tumor-specific CD8+ T cells in an IFN-γ–dependent manner. Conversely, intratumor depletion of either NK cells or IFN-γ during tumor progression disrupts CD8+ cell–mediated tumor rejection, suggesting that the tumor is the essential site for the crosstalk between NK and CD8+ cells. Furthermore, IFNG-deficient NK cells fail to effectively activate CD8+ T cells, suggesting IFN-γ plays an important role in NK-mediated activation of cytotoxic T lymphocytes (CTLs). Our findings establish a direct role for LIGHT in NK activation/expansion and a critical helper role of activated NK cells in priming CD8+ T cells and breaking T-cell tolerance at the tumor site.

scholarly journals Association of HLA Genotype With T-Cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus–Coinfected Women

2019 ◽  
Vol 221 (7) ◽  
pp. 1156-1166
Author(s):  
Andrea A Z Kovacs ◽  
Naoko Kono ◽  
Chia-Hao Wang ◽  
Daidong Wang ◽  
Toni Frederick ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
The Relationship

Abstract Background Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus . Methods We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10. Results Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, −6.6% [P = .002]; CD4 T cells, −2.7% [P = .007]), C*18:01 (CD8 T cells, −6.6%; P &lt; .0008) and DRB1*13:01 (CD4 T cells, −2.7%; P &lt; .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P &lt; .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03. Conclusion These findings suggest that a person’s HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.

scholarly journals Gamma Interferon Responses of CD4 and CD8 T-Cell Subsets Are Quantitatively Different and Independent of Each Other during Pulmonary Mycobacterium bovis BCG Infection

2007 ◽  
Vol 75 (5) ◽  
pp. 2244-2252 ◽  
Author(s):  
Patricia Ngai ◽  
Sarah McCormick ◽  
Cherrie Small ◽  
Xizhong Zhang ◽  
Anna Zganiacz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Mycobacterial Infection ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) is a key cytokine in host defense against intracellular mycobacterial infection. It has been believed that both CD4 and CD8 T cells are the primary sources of IFN-γ. However, the relative contributions of CD4 and CD8 T-cell subsets to IFN-γ production and the relationship between CD4 and CD8 T-cell activation have not been examined. By using a model of pulmonary mycobacterial infection and various immunodetection assays, we found that CD4 T cells mounted a much stronger IFN-γ response than CD8 T cells at various times after mycobacterial infection, and this pronounced IFN-γ production by CD4 T cells was attributed to both greater numbers of antigen-specific CD4 T cells and a greater IFN-γ secretion capacity of these cells. By using major histocompatibility complex class II-deficient or CD4-deficient mice, we found that the lack of CD4 T cells did not negatively affect primary or secondary CD8 T-cell IFN-γ responses. The CD8 T cells activated in the absence of CD4 T cells were capable of immune protection against secondary mycobacterial challenge. Our results suggest that, whereas both CD4 and CD8 T cells are capable of IFN-γ production, the former represent a much greater cellular source of IFN-γ. Moreover, during mycobacterial infection, CD8 T-cell IFN-γ responses and activation are independent of CD4 T-cell activation.

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