Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory

Development of tissue-resident memory (TRM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5hi PD-1hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R−/−) fail to become bTRM. IL-21+ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R−/− brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack TRM core signature genes. CD4 T cell–deficient and IL21R−/− brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell–depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5hi PD-1hi CD4 T cells in the brain produce IL-21, which drives CD8 bTRM differentiation in response to a persistent viral infection.

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Rejection of porcine islet xenografts mediated by CD4+ T cells activated through the indirect antigen recognition pathway

Xenotransplantation ◽

10.1034/j.1399-3089.2002.01070.x ◽

2002 ◽

Vol 9 (6) ◽

pp. 393-401 ◽

Cited By ~ 33

Author(s):

Barbara J. Olack ◽

Andrés Jaramillo ◽

Nicholas D. Benshoff ◽

Zahid Kaleem ◽

Carol J. Swanson ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Antigen Recognition ◽

Porcine Islet

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Lineage-Plasticity and Inflammatory Change of Human FoxP3+ Regulatory T Cells in Acute Viral Infection: Implication in Immune-Mediated Tissue Injury

Blood ◽

10.1182/blood.v124.21.4132.4132 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4132-4132

Author(s):

Yoon Seok Choi ◽

Jeewon Lee ◽

Ik-Chan Song ◽

Deog-Yeon Jo ◽

Eui-Cheol Shin

Keyword(s):

T Cells ◽

Viral Infection ◽

Treg Cell ◽

Liver Damage ◽

Cd4 T Cells ◽

Treg Cells ◽

Suppressive Activity ◽

Suppressive Function ◽

Acute Viral Infection ◽

Tnf Α

Abstract FoxP3+ CD4+CD25hi regulatory T (Treg) cells play a major role in maintaining the immune homeostasis by preventing the activation of self-reactive T cells as well as in controlling a series of immune responses in viral infections. Recent studies suggest that lineage-commitment of CD4+T cells, including Treg cells, is not a fixed fate, rather a status with a wide range of plasticity. Functional changes and lineage-plasticity of Treg cells during acute viral infection, especially of human, have not been reported so far. Herein, we investigated whether Treg cells show the functional plasticity and whether such changes can affect the regulation of immunopathology in a human acute viral infection. As a model of human acute viral infection, we used a cohort of patients with acute hepatitis A (AHA), since tissue (liver) injury in AHA is mediated exclusively by activated T cells, not by direct cytopathic effect of virus. To assess the plasticity of Treg cell lineage, first, we examined the production of a variety of inflammatory cytokines from Treg cells following T cell receptor (TCR) stimulation of peripheral blood lymphocytes with anti-CD3/CD28 antibody, using intracellular cytokine staining and multicolor flow cytometry. We found that a significant proportion of FoxP3+ CD4+CD25hi Treg cells produced TNF-α following TCR stimulation in patients with AHA, but not in heathy subjects. Analyses at multiple time points during the course of infection showed that TNF-α production from Treg cells decreased in convalescent phase. Likewise, we observed that liver-infiltrating Treg cells also produced TNF-α after TCR stimulation. Moreover, highly-purified CD4+CD25hiCD127lo/-Treg cells could also produce TNF-α following TCR stimulation, indicating that Treg cells of AHA patients can produce TNF-α in direct response to TCR stimulation. Next, to exclude the possibility that TNF-α might be secreted from transiently FoxP3-expressing activated non-Treg CD4+ T cells, we examined the expression level of CD127 on TNF-α-secreting FoxP3+ CD4+ T cells. TNF-α+ Treg cells expressed CD127 in the level similar to conventional TNF-α- counterpart, and CD127 expression levels of both Treg populations were much lower than FoxP3- CD4+ T cells. Furthermore, DNA methylation analysis of Treg cell-specific demethylated region (TSDR) after sorting TNF-α+ Treg cells revealed completely demethylated pattern in highly conserved CpG island of FOXP3 gene. These findings support that TNF-α is produced from bona fide Treg cells, not from FoxP3-expressing activated non-Treg CD4+T cells. In analysis of immunophenotypes, TNF-α+ Treg cells were enriched in CD45RA-FoxP3lo population, implying their reduced in vivo suppressive activity. Along with the lower level of FoxP3, TNF-α+ Treg cells showed lower level of CD39 expression, a surrogate marker of Treg cell suppressive activity, compared to TNF-α- Treg cells. Furthermore, TNF-α+Treg cells showed a robust evidence of lineage-plasticity toward Th17 lineage, expressing a key transcription factor RORγt. Consistently, they expressed CCR6 and co-produced IL-17A following TCR stimulation, which are the hallmark of Th17 effector function. To analyze the clinical implication of attenuate suppressive function and plasticity shown by TNF-α+ Treg cells, we examined correlation between production of proinflammatory cytokines from Treg cells and severity of liver damage in AHA. As a result, proportion of TNF-α-producing Treg cells closely and linearly correlated with severity of liver damage, suggesting the critical role of TNF-α+ Treg cells in the immunopathogenesis of AHA. However, Treg cell suppression assay in the absence or presence of anti-TNF-α antibody showed that Treg cell suppressive function was not affected by TNF-α blockade. This indicates that attenuated function of TNF-α+Treg cells is not attributed simply to production of a kind of inflammatory cytokine, rather to more complicated reprogramming mechanism. Taken together, these data provide a clear evidence of attenuated suppressive activity and Th17-toward lineage plasticity of FoxP3+ Treg cells, represented by TNF-α production, in a human acute viral infection. Also, we suggest one possible mechanism that lineage plasticity and inflammatory changes of Treg cells could be implicated in the immunopathogenesis of human diseases. Disclosures No relevant conflicts of interest to declare.

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T Cell–Intrinsic CX3CR1 Marks the Most Differentiated Effector CD4+ T Cells, but Is Largely Dispensable for CD4+ T Cell Responses during Chronic Viral Infection

ImmunoHorizons ◽

10.4049/immunohorizons.2000059 ◽

2020 ◽

Vol 4 (11) ◽

pp. 701-712

Author(s):

Nathália V. Batista ◽

Yu-Han Chang ◽

Kuan-Lun Chu ◽

Kuan Chung Wang ◽

Mélanie Girard ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Viral Infection ◽

Cd4 T Cells ◽

T Cell Responses ◽

Cd4 T Cell ◽

Chronic Viral Infection ◽

Cell Responses

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CCR7 Ligands Induced Expansion of Memory CD4+ T Cells and Protection from Viral Infection

Immune Network ◽

10.4110/in.2003.3.1.29 ◽

2003 ◽

Vol 3 (1) ◽

pp. 29

Author(s):

Seong-Kug Eo ◽

Jeong-Gon Cho

Keyword(s):

T Cells ◽

Viral Infection ◽

Cd4 T Cells ◽

Memory Cd4 T Cells

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Acquisition of FOXP3 Expression by Human Effector CD4+ T Cells Is a Natural Consequence of Antigen Recognition.

Blood ◽

10.1182/blood.v108.11.870.870 ◽

2006 ◽

Vol 108 (11) ◽

pp. 870-870

Author(s):

J. Joseph Melenhorst ◽

Phillip Scheinberg ◽

David R. Ambrozak ◽

Nancy F. Hensel ◽

Daniel C. Douek ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Foxp3 Expression ◽

Cell Receptor ◽

Antigen Recognition ◽

Natural Consequence ◽

Antigen Stimulation ◽

Hla Dr

Abstract Recent data suggest that CD4+CD25+FOXP3+ regulatory T cells (TR) can be generated from CD4+CD25−FOXP3− T cells in the periphery. We studied the induction of CD4+CD25+FOXP3+ T cells during the course of immune responses to cytomegalovirus, tetanus toxoid, purified protein derivative and streptokinase. Peripheral blood mononuclear cells (PBMC) from healthy donors were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFDA) and stimulated with antigen for 6–7 days. Cells were stained for CD3, CD4, CD25, HLA-DR, CD38, and intracellular FOXP3. Responders to antigens had proliferating (CFDA[dim]) CD4+ T cells expressing CD25 and the activation markers CD38 and HLA-DR. In PBMC from five donors, a median of 37% (range 9–57%) of the proliferating fraction expressed FOXP3 (figure) which mostly co-expressed CD25, HLA-DR and CD38, suggesting that FOXP3 expression is the consequence of cellular activation triggered through the T cell receptor. Since all of these healthy subjects had circulating, pre-existing CD4+CD25+FOXP3+ T cells in the absence of ex vivo antigen stimulation, however, it was possible that these gave rise to the FOXP3+ responder cells. Antigen stimulation of PBMC from three donors aged 69–70 years with no detectable CD4+CD25+FOXP3+ T cells also induced proliferating activated CD4+CD25+FOXP3+ T cells, excluding the possibility that a pre-existing pool of FOXP3+ T cells gave rise to this population. Subsequently, we sorted CD4+ T cells that proliferated in response to antigen by flow cytometry on the basis of FOXP3 expression to sequence the T cell receptor-β CDR3 regions and to establish the T cell clonotype structure of proliferating FOXP3-positive and -negative T cells. These data also indicate that effector CD4+ T cells acquire FOXP3 expression during the course of an immune response. Based on these and previously reported findings, we propose that the acquisition of FOXP3 expression by effector CD4+ T cells is a natural consequence of antigen recognition that serves as a specific regulatory feedback system. Induction of FOXP3 expression in proliferating CD4+ T cells in response to T cell receptor triggering Induction of FOXP3 expression in proliferating CD4+ T cells in response to T cell receptor triggering

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From specificity to degeneracy to molecular mimicry: Antigen recognition of human autoreactive and pathogen-specific CD4+ T cells

Journal of Neuroimmunology ◽

10.1016/s0165-5728(98)91382-0 ◽

1998 ◽

Vol 90 (1) ◽

pp. 34

Author(s):

B. Hemmer ◽

C. Pinilla ◽

B. Gran ◽

H. McFarland ◽

R. Houghten ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Molecular Mimicry ◽

Antigen Recognition

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Rapid Expansion of Virus-Specific CD4+ T Cell Types in the CNS of Susceptible Mice Infected with Theiler’s Virus

International Journal of Molecular Sciences ◽

10.3390/ijms21207719 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7719

Author(s):

Hyun Seok Kang ◽

Wanqiu Hou ◽

Byung S. Kim

Keyword(s):

T Cells ◽

T Cell ◽

Viral Infection ◽

Cd4 T Cells ◽

Demyelinating Disease ◽

Cell Types ◽

Rapid Expansion ◽

Infection Model ◽

Dependent Manner ◽

Encephalomyelitis Virus

The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) induces a T cell-mediated demyelinating disease. This system has been studied as a relevant infection model for multiple sclerosis (MS). Therefore, defining the type of T cell responses and their functions is critically important for understanding the relevant pathogenic mechanisms. In this study, we adoptively transferred naive VP2-specific TCR-Tg CD4+ T cells into syngeneic susceptible SJL mice and monitored the development of the disease and the activation and proliferation of CD4+ T cells during the early stages of viral infection. The preexisting VP2-specific naive CD4+ T cells promoted the pathogenesis of the disease in a dose-dependent manner. The transferred VP2-specific CD4+ T cells proliferated rapidly in the CNS starting at 2–3 dpi. High levels of FoxP3+CD4+ T cells were found in the CNS early in viral infection (3 dpi) and persisted throughout the infection. Activated VP2-specific FoxP3+CD4+ T cells inhibited the production of IFN-γ, but not IL-17, via the same VP2-specific CD4+ T cells without interfering in proliferation. Thus, the early presence of regulatory T cells in the CNS with viral infection may favor the induction of pathogenic Th17 cells over protective Th1 cells in susceptible mice, thereby establishing the pathogenesis of virus-induced demyelinating disease.

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