scholarly journals Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection

2015 ◽  
Vol 212 (9) ◽  
pp. 1405-1414 ◽  
Author(s):  
Nelson D. Glennie ◽  
Venkata A. Yeramilli ◽  
Daniel P. Beiting ◽  
Susan W. Volk ◽  
Casey T. Weaver ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Memory T Cells ◽  
Critical Role ◽  
Parasitic Infection ◽  
Dependent Manner ◽  
Peripheral Tissues ◽  
Circulating T Cells ◽  
Memory Cd4 T Cells

Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection after disease resolution, effective immune protection has not yet been achieved by human vaccines. Although circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFN-γ and remain resident in the skin when transplanted by skin graft onto naive mice. They function to recruit circulating T cells to the skin in a CXCR3-dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells.

scholarly journals Anergy in Peripheral Memory Cd4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor

2001 ◽  
Vol 194 (6) ◽  
pp. 719-732 ◽  
Author(s):  
Saied Mirshahidi ◽  
Ching-Tai Huang ◽  
Scheherazade Sadegh-Nasseri
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Critical Role ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Memory Cd4 T Cells

Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4+ T cells can be rendered anergic by presentation of low densities of agonist peptide–major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2–reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti–CTLA-4 blocking antibody restored anergy in vivo.

scholarly journals Tolerance induction in memory CD4 T cells is partial and reversible

2020 ◽  
Author(s):  
Joshua I Gray ◽  
Shaima Al-Khabouri ◽  
Fraser Morton ◽  
Eric T Clambey ◽  
Laurent Gapin ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Tolerance Induction ◽  
Peripheral Tissues ◽  
Repair Enzymes ◽  
Memory Cd4 T Cells ◽  
Secondary Lymphoid Organs ◽  
Secondary Activation ◽  
Low Expression

AbstractMemory T cells respond rapidly in part because they are less reliant on heightened levels of costimulatory molecules. This presents challenges to silencing memory T cells in tolerance strategies for autoimmunity or allergy. We find that memory CD4 T cells generated by infection or immunisation survive secondary activation with antigen delivered without adjuvant, regardless of their location in secondary lymphoid organs or peripheral tissues. These cells were, however, functionally altered following a tertiary immunisation with antigen and adjuvant, proliferating poorly but maintaining their ability to produce inflammatory cytokines. Transcriptional and cell cycle analysis of these memory CD4 T cells suggest they are unable to commit fully to cell division potentially because of low expression of DNA repair enzymes. In contrast, these memory CD4 T cells could proliferate following tertiary reactivation by viral re-infection. These data suggest that tolerance induction in memory CD4 T cells is partial and can be reversed.

scholarly journals Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

2019 ◽  
Author(s):  
Eddie Cano-Gamez ◽  
Blagoje Soskic ◽  
Theodoros I. Roumeliotis ◽  
Ernest So ◽  
Deborah J. Smyth ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Effector Memory ◽  
Dependent Manner ◽  
Rna Seq ◽  
Cytokine Responses ◽  
Regulated Gene Expression ◽  
Memory Cd4 T Cells

AbstractNaïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naïve and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naïve to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.

scholarly journals Skin-Resident Memory T Cells: Pathogenesis and Implication for the Treatment of Psoriasis

2021 ◽  
Vol 10 (17) ◽  
pp. 3822
Author(s):  
Trung T. Vu ◽  
Hanako Koguchi-Yoshioka ◽  
Rei Watanabe
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Inflammatory Diseases ◽  
Adaptive Immune Response ◽  
Psoriatic Skin ◽  
Peripheral Tissues ◽  
Potential Index ◽  
Circulating T Cells ◽  
Chronic Skin ◽  
Resident Memory T Cells

Tissue-resident memory T cells (TRM) stay in the peripheral tissues for long periods of time, do not recirculate, and provide the first line of adaptive immune response in the residing tissues. Although TRM originate from circulating T cells, TRM are physiologically distinct from circulating T cells with the expression of tissue-residency markers, such as CD69 and CD103, and the characteristic profile of transcription factors. Besides defense against pathogens, the functional skew of skin TRM is indicated in chronic skin inflammatory diseases. In psoriasis, IL-17A-producing CD8+ TRM are regarded as one of the pathogenic populations in skin. Although no licensed drugs that directly and specifically inhibit the activity of skin TRM are available to date, psoriatic skin TRM are affected in the current treatments of psoriasis. Targeting skin TRM or using TRM as a potential index for disease severity can be an attractive strategy in psoriasis.

scholarly journals Ex Vivo Phenotype and Frequency of Influenza Virus-Specific CD4 Memory T Cells

2004 ◽  
Vol 78 (13) ◽  
pp. 7284-7287 ◽  
Author(s):  
Michaela Lucas ◽  
Cheryl L. Day ◽  
Jessica R. Wyer ◽  
Sharon L. Cunliffe ◽  
Andrew Loughry ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Class Ii ◽  
Low Frequencies ◽  
Tetramer Staining ◽  
Specific Memory ◽  
Memory Cd4 T Cells

ABSTRACT Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct “central memory” CD62L+ phenotype.

scholarly journals Pathological T Helper Polarization Requires Pre-existing Cross-Reactive Memory T Cells

2021 ◽  
Author(s):  
David Usharauli ◽  
Tirumalai Kamala
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Physiological Process ◽  
T Helper ◽  
Mhc Ii ◽  
Cytokine Milieu ◽  
Spiral Model ◽  
Memory Cd4 T Cells

Naive CD4+ T cells engage cognate peptide MHC-II complexes (pMHC-IIs) to differentiate and acquire one of several T helper (Th) fates whose specific trajectories are guided by a dynamic cytokine milieu that develops in response to antigenic entity. This physiological process is often erroneously conflated with a pathological one termed Th polarization. Using the SPIRAL model, we argue here that unlike Th fate choice, innate signaling alone is insufficient to initiate Th polarization in naive CD4+ T cells, that it instead develops from pre-existing memory CD4+ T cells that express cross-reactive TCRs, and that it inevitably leads to immunopathology.

scholarly journals ID:3002 Notch-mediated control of memory T cells against cancer cells

2017 ◽  
Vol 4 (S) ◽  
pp. 12
Author(s):  
Koji Yasutomo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Term Survival ◽  
Long Term Survival ◽  
Memory Cd4 T Cells

T cells recognize an antigen presented by self-MHC, and the part of initially activated T cells differentiate toward memory T cells. T cells also recognize cancer cells leading to generation of memory T cells against cancer-derived antigens although the activity of T cells are frequently suppressed by various factors. The release from T cell inhibitory factors could allow T cells to respond to cancer cells. However, it remains unclear which molecules are required for long-term survival of memory T cells and generation of memory T cells against cancer cells. Notch functions as a regulator for fate decision, activation and survival of immune cells. We have demonstrated the roles of Notch in mature T cell differentiation and found that Notch signaling is essential for the maintenance of memory CD4 T cells. The inhibition of Notch disturbs the survival of memory CD4 T cells. The effect of Notch on T cell survival depended on glucose uptake through cell surface Glut1 expression. We revealed that Notch is crucial for the long-term survival of memory T cells against cancer cells and suppression of Notch signaling reduced the tumor antigen-specific killing of cancer cells. Those data demonstrate that Notch is pivotal for the maintenance of memory T cells against cancer cells and suggest that activation of Notch signaling might be advantageous to cancer immunotherapy.

scholarly journals Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation

2009 ◽  
Vol 206 (2) ◽  
pp. 371-385 ◽  
Author(s):  
Muzlifah Haniffa ◽  
Florent Ginhoux ◽  
Xiao-Nong Wang ◽  
Venetia Bigley ◽  
Michal Abel ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Hematopoietic Stem ◽  
Memory Cd4 T Cells

Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow–derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45+HLA-DR+ cells: CD1a+CD14− DC, CD1a−CD14+ DC, and CD1a−CD14+FXIIIa+ macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a+ and CD14+ DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4+ T cells, macrophages induce cytokine expression in memory CD4+ T cells and activation and proliferation of CD8+ T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells.

scholarly journals Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis

2000 ◽  
Vol 191 (2) ◽  
pp. 375-380 ◽  
Author(s):  
Hisaya Akiba ◽  
Yasushi Miyahira ◽  
Machiko Atsuta ◽  
Kazuyoshi Takeda ◽  
Chiyoko Nohara ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Th2 Cells ◽  
Mouse Strains ◽  
T Helper

Infection of inbred mouse strains with Leishmania major is a well characterized model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and OX40, which belong to the tumor necrosis factor receptor superfamily, in the development of Th1 and Th2 cells in vivo, we administered monoclonal antibody (mAb) against their ligands, CD70, CD30 ligand (L), 4-1BBL, and OX40L, to mice infected with L. major. Whereas anti-CD70, anti-CD30L, and anti–4-1BBL mAb exhibited no effect in either susceptible BALB/c or resistant C57BL/6 mice, the administration of anti-OX40L mAb abrogated progressive disease in BALB/c mice. Flow cytometric analysis indicated that OX40 was expressed on CD4+ T cells and OX40L was expressed on CD11c+ dendritic cells in the popliteal lymph nodes of L. major–infected BALB/c mice. In vitro stimulation of these CD4+ T cells showed that anti-OX40L mAb treatment resulted in substantially reduced production of Th2 cytokines. Moreover, this change in cytokine levels was associated with reduced levels of anti–L. major immunoglobulin (Ig)G1 and serum IgE. These results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in BALB/c mice by suppressing the development of Th2 responses, substantiating a critical role of OX40–OX40L interaction in Th2 development in vivo.

IFN-λ1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses in human naive and memory T cells

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5829-5838 ◽  
Author(s):  
Jihong Dai ◽  
Nicholas J. Megjugorac ◽  
Grant E. Gallagher ◽  
Raymond Y. L. Yu ◽  
Grant Gallagher
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Effector Memory ◽  
Immunomodulatory Effects ◽  
Specific Receptor ◽  
Effector Memory T Cells ◽  
Th2 Responses ◽  
Gata3 Expression ◽  
Memory Cd4 T Cells

Abstract IFN-λ1 (IL-29) plays a novel, emerging role in the inhibition of human Th2 responses. Here, we demonstrate that both naive and memory human CD4+ T cells express mRNA for the IFN-λ1–specific receptor, IL-28Rα, and are responsive to IFN-λ1. Expression of Th2 cytokines (IL-4 and IL-13) was suppressed in naive and memory CD4+ T cells by IFN-λ1, without affecting their proliferation. Further, acquisition of IL-4Rα expression after stimulation was inhibited by IFN-λ1, as was GATA3 expression. Finally, IFN-λ1 diminished the change in cell-surface phenotype that accompanies differentiation of “central memory” T cells into “effector memory” T cells. Taken together, our data describe unique immunomodulatory effects of IFN-λ1 and identify novel mechanisms for the reduction of existing Th2 responses and the regulation of new ones, in circulating naive and memory CD4+ T cells.

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