scholarly journals Functional Characterization of Ly49+CD8 T-Cells in Both Normal Condition and During Anti-Viral Response

2021 ◽  
Vol 11 ◽  
Author(s):  
Dmytro Shytikov ◽  
Deepak Rohila ◽  
Dan Li ◽  
Pengfei Wang ◽  
Mei Jiang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Functional Characterization ◽  
Dynamic Regulation ◽  
Memory Cd8 T Cells ◽  
Viral Response ◽  
Lcmv Infection

The role of Ly49+CD8 T-cells in the immune system is not clear. Previously, several papers suggested Ly49+CD8 T-cells as immunosuppressors, while multiple studies also suggested their role as potent participants of the immune response. The mechanism of Ly49 expression on CD8 T-cells is also not clear. We investigated phenotype, functions, and regulation of Ly49 expression on murine CD8 T-cells in both normal state and during LCMV infection. CD8 T-cells express different Ly49 receptors compared with NK-cells. In intact mice, Ly49+CD8 T-cells have a phenotype similar to resting central memory CD8 T-cells and do not show impaired proliferation and cytokine production. Conventional CD8 T-cells upregulate Ly49 receptors during TCR-induced stimulation, and IL-2, as well as IL-15, affect it. At the same time, Ly49+CD8 T-cells change the Ly49 expression profile dramatically upon re-stimulation downregulating inhibitory and upregulating activating Ly49 receptors. We observed the expression of Ly49 receptors on the virus-specific CD8 T-cells during LCMV infection, especially marked in the early stages, and participation of Ly49+CD8 T-cells in the anti-viral response. Thus, CD8 T-cells acquire Ly49 receptors during the T-cell activation and show dynamic regulation of Ly49 receptors during stimulation.

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.

scholarly journals Role of CD8+ T cells in crescentic glomerulonephritis

2019 ◽  
Vol 35 (4) ◽  
pp. 564-572 ◽  
Author(s):  
Anqun Chen ◽  
Kyung Lee ◽  
Tianjun Guan ◽  
John Cijiang He ◽  
Detlef Schlondorff
Keyword(s):  
T Cells ◽  
Immune Complex ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Crescentic Glomerulonephritis ◽  
Rapidly Progressive Glomerulonephritis ◽  
Inflammatory Cells ◽  
Gain Access

Abstract Crescentic glomerulonephritis (cGN) comprises three main types according to the pathogenesis and immunofluorescence patterns: anti-glomerular basement membrane antibody cGN, vasculitis-associated cGN and post-infectious immune complex cGN. In this brief review of the immune-pathogenesis of cGN, the focus is mainly on the role of CD8+ T cells in the progression of cGN. Under control conditions, Bowman’s capsule (BC) provides a protected immunological niche by preventing access of cytotoxic CD8+ T cells to Bowman’s space and thereby podocytes. Even in experimental nephrotoxic nephritis, leukocytes accumulate around the glomeruli, but remain outside of BC, as long as the latter remains intact. However, when and where breaches in BC occur, the inflammatory cells can gain access to and destroy podocytes, thus converting cGN into rapidly progressive glomerulonephritis (RPGN). These conclusions also apply to human cGN, where biopsies show that loss of BC integrity is associated with RPGN and progression to end-stage kidney disease. We propose a two-hit hypothesis for the role of cytotoxic CD8+ T cells in the progression of cGN. The initial insult occurs in response to the immune complex formation or deposition, resulting in local capillary and podocyte injury (first hit). The injured podocytes release neo-epitopes, eventually causing T-cell activation and migration to the glomerulus. Upon generation of breaches in BC, macrophages and CD8+ T cells can now gain access to the glomerular space and destroy neo-epitope expressing podocytes (second hit), resulting in RPGN. While further investigation will be required to test this hypothesis, future therapeutic trials should consider targeting of CD8+ T cells in the therapy of progressive cGN.

T Cell Activation and Regulation in Graft-Versus-Host Disease: Integral Role of CD28, CTLA4 and GITR Splice Variants.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3054-3054
Author(s):  
Yuji Miura ◽  
Christopher J. Thoburn ◽  
Emilie C. Bright ◽  
Elizabeth C. Matsui ◽  
William H. Matsui ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Splice Variants ◽  
Treg Cells ◽  
Mrna Splice ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) is a serious, life-threatening complication that occurs following allogeneic (allo) bone marrow transplantation (BMT). The use of non-specific immunosuppression or T cell depletion has reduced the incidence of GVHD but at the expense of increased rates of infection and leukemic relapse. Modulation of the major costimulatory pathway (CD28/CTLA4:B7) involved in T cell activation and regulation may lead to specific immune tolerance in the absence of global non-specific immunosuppression. The identification of mRNA splice variants encoding for soluble forms of CD28, CTLA4 and GITR suggests that costimulation of T cells is complex and is not limited to cell-cell contact. The present studies examined the hypothesis that the onset of GVHD and the re-establishment of immune tolerance correlate with the expression levels of these costimulatory molecules. mRNA transcript levels for the soluble (s) and full-length (fl; cell surface associated) variants assessed by quantitative PCR, were temporally examined in peripheral blood lymphocytes (PBLs) from patients undergoing alloBMT (n=38) or autologous (auto) BMT (n=39) with the induction of autoGVHD by cyclosporin A treatment post-transplant. Levels of s and fl CD28 mRNA transcripts in PBLs were significantly increased (>1.5 fold, P<0.05) in patients developing either allo or autoGVHD compared to patients who do not develop GVHD. s and flCTLA4 levels in patients at the onset of allo and autoGVHD were significantly decreased compared to healthy controls (n=22) (>2.3-fold, P<0.01). s and flCTLA4 expression in patients with autoGVHD was significantly decreased compared to patients without autoGVHD (>2.1-fold). sCTLA4 expression in patients with alloGVHD was significantly decreased than patients without alloGVHD. Interestingly, temporal analysis revealed that the levels for sCTLA4 paralleled the recovery from GVHD implicating an active process in the establishment of non-responsiveness. CD28, CTLA4 and GITR s and fl mRNA levels in CD4+CD25+ T regulatory (Treg) cells from allo and autoBMT patients were significantly increased (7-, 41- or 22-fold, P<0.01) compared to the CD4+CD25− subset. Additional studies attempted to identify the potential role of the sCTLA4 protein (encoded by the mRNA splice variant) on the regulation of the lymphocyte response mediated by Treg cells. Addition of the Treg cells to a mixed lymphocyte reaction suppressed the proliferative response of CD8+ T cells to alloantigens (75% suppression; >4 fold reduction of 3H-thymidine incorporation). However, pretreatment of the Treg subset with short interfering RNA (siRNA) to knockdown sCTLA4 gene (confirmed by quantitative PCR) significantly reduced the ability of these cells to suppress the response (minimal suppression was detected, 6%). In vitro siRNA studies also indicated that Treg cells with inhibited sCTLA4 expression were unable to suppress the response of IL-2-stimulated autoreactive CD8+ T cells. Taken together, the results indicate that increased expression of CTLA4 (soluble and cell-surface associated) and the “negative” signal delivered by this molecule to the T cell may regulate the development of GVHD and help to re-establish self tolerance after BMT. Defining the role of costimulation and the modulation of this pathway on immune recognition and regulation not only provides opportunities to enhance the re-establishment of tolerance but also may help to intensify anti-tumor immunotherapeutic strategies.

scholarly journals Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction

2014 ◽  
Vol 211 (10) ◽  
pp. 2047-2059 ◽  
Author(s):  
Peter D. Kurktschiev ◽  
Bijan Raziorrouh ◽  
Winfried Schraut ◽  
Markus Backmund ◽  
Martin Wächtler ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis B ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Viral Infections ◽  
Critical Role ◽  
Interferon Γ ◽  
Strongly Correlated

The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet–deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet+ CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.

scholarly journals Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection

2006 ◽  
Vol 203 (10) ◽  
pp. 2263-2269 ◽  
Author(s):  
Vaiva Vezys ◽  
David Masopust ◽  
Christopher C. Kemball ◽  
Daniel L. Barber ◽  
Leigh A. O'Mara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Persistent Infection ◽  
Chronic Infection ◽  
Cell Activation ◽  
Viral Infections ◽  
Cd8 T Cell ◽  
Memory Cd8 T Cells

Numerous microbes establish persistent infections, accompanied by antigen-specific CD8 T cell activation. Pathogen-specific T cells in chronically infected hosts are often phenotypically and functionally variable, as well as distinct from T cells responding to nonpersistent infections; this phenotypic heterogeneity has been attributed to an ongoing reencounter with antigen. Paradoxically, maintenance of memory CD8 T cells to acutely resolved infections is antigen independent, whereas there is a dependence on antigen for T cell survival in chronically infected hosts. Using two chronic viral infections, we demonstrate that new naive antigen-specific CD8 T cells are primed after the acute phase of infection. These newly recruited T cells are phenotypically distinct from those primed earlier. Long-lived antiviral CD8 T cells are defective in self-renewal, and lack of thymic output results in the decline of virus-specific CD8 T cells, indicating that newly generated T cells preserve antiviral CD8 T cell populations during chronic infection. These findings reveal a novel role for antigen in maintaining virus-specific CD8 T cells during persistent infection and provide insight toward understanding T cell differentiation in chronic infection.

Histone Deacetylase 6 (HDAC6) Influences T-Cell Activation and Survival: Implications For Cancer Immunotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1050-1050
Author(s):  
Andressa Sodre Laino ◽  
David M Woods ◽  
Fengdong Cheng ◽  
Hongwei Wang ◽  
Eduardo M. Sotomayor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Wild Type ◽  
T Cell Survival

Abstract The role of histone deacetylases (HDACs) as epigenetic regulators of immune function is becoming increasingly clear. Recently, the role of specific HDACs in orchestrating T-cell maturation, survival and function has begun to emerge, giving rationale to selective therapy to direct immune responses in different disease settings, including cancer. In particular, HDAC6 has recently been characterized as a negative regulator of regulatory T-cell suppressive activity (de Zoeten, Molecular and Cellular Biology, 2011). Here we report an expanded, novel role of HDAC6 in regulating T-cell survival and activation. First, the relative expression of the eleven classic HDACs was evaluated in resting and activated T-cells from mouse and human samples. It was found that the majority of HDACs decrease in expression following activation, including HDAC6. Next, in a HDAC6KO mouse model, it was found that T-cells lacking HDAC6 had skewed survival when compared to wild-type murine T-cells. This difference seems to be the result of an increased CD4+ T-cells population in the lymph nodes, with a concomitant decrease in viable CD8+ T-cells. To determine whether this population skewing was the consequence of defects in HDAC6KO mice T-cell development, wild-type murine T-cells were treated with an isotype-selective HDAC6 inhibitor. The results seen in HDAC6KO T-cells were recapitulated when wild-type T-cells were activated and treated with HDAC6 specific inhibitors, indicating a role of HDAC6 outside of thymic development in promoting CD4+ T-cell survival at the expense of CD8+ T-cells. Interestingly, it was found that activated CD4+ T-cells displayed decreased expression of the apoptosis signaling receptor FAS after HDAC6 inhibition while no differences were observed in CD8+ T-cells under the same conditions. In addition to these results implicating HDAC6 in regulating T-cell survival, expression of surface markers was altered in both CD8+ and CD4+ T-cells, including enhanced expression of the activation molecule CD69 in stimulated T-cells treated with an isotype-selective HDAC6 inhibitor. Finally, in vivo studies in tumor-bearing HDAC6KO mice revealed a significantly delayed in tumor progression. Similar results were observed in lymphoma-bearing mice treated with HDAC6 specific inhibitors. Taken together, this data shows that HDACs are dynamic in expression with regards to T-cell activation state. More specifically, we have unveiled hereto-unexplored roles of HDAC6 in regulating T-cell survival and function, pointing at this specific HDAC as an appealing target to harness T-cell immunity in hematologic malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lenalidomide Enhances Human Alloresponses By Increasing Proliferation of Effector Memory CD8 T Cells with Enhanced Polyfunctional Effector Capacity and a Unique Gene Expression Profile

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1103-1103
Author(s):  
Caroline Mary Besley ◽  
Eleni Kotsiou ◽  
Robert Petty ◽  
Ajanthah Sangaralingum ◽  
Rifca Le Dieu ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Effector Memory ◽  
Altered Expression ◽  
Memory Cd8 T Cells ◽  
Tnf Α

Abstract Introduction IMiDs like lenalidomide have immunostimulatory effects and therefore the potential to reduce relapse after allogeneic haematopoietic cell transplant (AHCT) by increasing graft-versus-tumour (GvT) effects. However, early clinical experience using IMiDs after AHCT has been limited by induction of graft-versus-host disease (GvHD). Although lenalidomide has been shown to augment mitogen-stimulated T cell responses, the effects of this drug on T cell alloresponses that mediate both GvT and GvHD have not been well defined. Better understanding of the immune mechanisms involved would facilitate tracking and manipulation of lenalidomide-potentiated alloresponses and could reveal ways to use the drug to maximise GvT without excess GvHD. Therefore we used an HLA-mismatched in vitro model to analyse in depth the effects of lenalidomide on functional human T cell alloresponses. Materials and Methods We cocultured CFSE-labelled PBMC from healthy donors with irradiated allogeneic PBMC in the presence of 1μM lenalidomide, vehicle control or following pre-incubation with 1μM lenalidomide for 24 hours. Functional alloresponses were quantified after 7-9 days of allo-coculture by flow cytometry. In addition, allo-coculture responders were flow-sorted into alloproliferative or non-proliferative fractions and extracted RNA used for gene expression profiling. Results Addition of lenalidomide to allo-cocultures increased the total number of responder cells (p<0.001) due primarily to increased proliferation (74% median increase) of allospecific responder CD8 (alloCD8) T cells (p<0.001). Proliferation kinetic analysis showed that lenalidomide did not increase the number of cell divisions of alloCD8 cells, but increased the CD8 allospecific precursor frequency within the responder cell pool (from a median of 2.6% to 10%, p<0.001) consistent with lowering the activation threshold of alloCD8 cells. A significant enrichment for effector memory phenotype was observed in these cells (median 48% increased to 59%, p<0.001). Addition of lenalidomide to allo-cocultures also increased the proportion of alloCD8 cells secreting TNF-α, IFN-γ and expressing CD107a, as well as polyfunctional effector cells (Fig. 1A). Although lenalidomide did not increase proliferation of CD4 cells, TNF-α production by proliferative CD4 T cells was increased suggesting they may contribute indirectly to CD8 alloresponses. Pre-treatment of stimulators, responders or both prior to allo-coculture did not result in increased alloCD8 proliferation, indicating that the drug must be present in the co-culture to exert an effect. Finally to assess whether lenalidomide exerted effects via potentiation of intrinsic alloproliferative pathways or by qualitatively different pathways we performed gene expression profiling of CD8 T cells sorted from allo-cocultures. As expected, alloCD8 cells from untreated allo-cocultures demonstrated >2-fold altered expression of >500 genes mostly associated with DNA synthesis and cellular proliferation when compared to non-proliferative CD8 cells. Lenalidomide-treated alloCD8 cells showed further increases in expression of many of these genes; however treatment also resulted in significant changes in expression of additional genes in alloCD8 cells compared to untreated alloCD8 cells (Fig 1B). These included >8 fold increases in expression of genes reported to potentiate T cell immune responses in other settings including PFKFB4,Pirin, and SOCS2 (part of the E3 ubiquitin ligase complex with cereblon), and >5 fold decreases in genes which can suppress T cell activation and memory differentiation including FAIM3 and PMCH. Conclusion We have shown for the first time that lenalidomide potentiates human alloresponses primarily by increasing alloproliferation of effector memory CD8 T cells. This likely results from altered expression of (i) multiple genes common to the intrinsic CD8 alloproliferative response and (ii) additional genes involved in the control of T cell activation and differentiation specific to lenalidomide-potentiated CD8 alloresponses. Furthermore treatment enhances the functional capacity of these cells by conferring greater polyfunctional effector potential. These findings could enable tracking of CD8 alloresponses induced by lenalidomide after AHCT and could inform novel clinical strategies for the use of the drug to augment GvT effects. Figure 1 Figure 1. Disclosures Gribben: Celgene: Research Funding; Pharmacyclics: Honoraria; Roche: Honoraria.

scholarly journals Chronic Porphyromonas gingivalis lipopolysaccharide induces adverse myocardial infarction wound healing through activation of CD8+ T-cells

2021 ◽  
Author(s):  
Yusra Zaidi ◽  
Alexa Corker ◽  
Valeriia Y. Vasileva ◽  
Kimberly Oviedo ◽  
Conner Graham ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Tissue Bank ◽  
Mouse Heart ◽  
Memory Cd8 T Cells ◽  
Wall Thinning

Oral and gum health have long been associated with incidence and outcomes of cardiovascular disease. Periodontal disease increases myocardial infarction (MI) mortality by seven-fold through mechanisms that are not fully understood. The goal of this study was to evaluate whether lipopolysaccharide (LPS) from a periodontal pathogen accelerates inflammation post-MI through memory T-cell activation. We compared 4 groups (no MI, chronic LPS, day 1 post-MI, and day 1 post-MI with chronic LPS (LPS+MI); n=68 mice) using the mouse heart attack research tool 1.0 database and tissue bank coupled with new analyses and experiments. LPS+MI increased total CD8+ T-cells in the left ventricle versus the other groups (p<0.05 versus all). Memory CD8+ T-cells (CD44+CD27+) were 10-fold greater in LPS+MI compared to MI alone (p=0.02). Interleukin (IL)-4 stimulated splenic CD8+ T-cells away from an effector phenotype and towards a memory phenotype, inducing secretion of factors associated with the Wnt/β-catenin signaling that promoted monocyte migration and decreased viability. To dissect the effect of CD8+ T-cells post-MI, we administered a major histocompatibility complex-I blocking antibody starting 7 days before MI, which prevented effector CD8+ T-cell activation without affecting the memory response. The reduction in effector cells diminished infarct wall thinning but had no effect on macrophage numbers or MertK expression. LPS+MI+IgG attenuated macrophages within the infarct without effecting CD8+ T-cells suggesting these two processes were independent. Overall, our data indicate that effector and memory CD8+ T-cells at post-MI day 1 are amplified by chronic LPS to potentially promote infarct wall thinning.

scholarly journals Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8+ but not CD4+ T cells

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Miwa Sasai ◽  
Ji Su Ma ◽  
Masaaki Okamoto ◽  
Kohei Nishino ◽  
Hikaru Nagaoka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Tcr Signaling

Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4+ and CD8+ T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8+ T cells is qualitatively different from that in CD4+ T cells, since CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8+ T cells, whereas those in CD4+ T cells were intact. PLCβ4-deficient CD8+ T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8+ T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8+ T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4+ and CD8+ T cells and selectively promotes CD8+ T cell–dependent adaptive immunity.

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