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

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.

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Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

International Journal of Molecular Sciences ◽

10.3390/ijms21176118 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6118 ◽

Cited By ~ 1

Author(s):

Marianna Szczypka

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Splice Variants ◽

Cell Activity ◽

Cell Functions ◽

Simultaneous Inhibition ◽

And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

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Characterisation of Human CD83 Expression on Immune Cells and Their Targeting with CD83 Antibodies to Prevent Graft Versus Host Disease in Allogeneic Haematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v126.23.3081.3081 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3081-3081

Author(s):

Derek NJ Hart ◽

Xinsheng Ju ◽

Zehra Elgundi ◽

Nirupama Verma ◽

Pablo Silveira ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Immune Cells ◽

Cell Activation ◽

Splice Variants ◽

Scid Mice ◽

Human Pbmc ◽

Graft Versus Host ◽

Equity Ownership

Abstract Introduction: CD83 is an important marker of activated dendritic cells (DC) but it is also expressed on other immune cells. Polyclonal anti-CD83 antibody depletes activated DC and prevents human peripheral blood mononuclear cell (PBMC) induced xenogeneic graft versus host disease (GVHD) in immunosuppressed SCID mice (J Exp Med 2009;206;387). We therefore generated a potential therapeutic human anti-CD83 mAb (3C12C), which had similar efficacy and T cell sparing effects in the same model (Leukemia 2015; in press). To investigate the specific immunosuppressive effect of 3C12C further, we undertook a comprehensive analysis of CD83 expression and its glycosylation pattern on various immune cell populations and tested the effect of 3C12C on T cell function using preclinical models, including a human CD83 (hCD83) knock in (KI) mouse. Methods: A panel of mouse and recombinant mAbs to hCD83 were used to analyse its expression by flow cytometry on resting and activated healthy donor PBMC. The expression of potential CD83 splice variants was examined by PCR. T cell expression was examined by flow cytometry and confocal microscopy after PHA, CD3/CD28 beads and allogeneic mixed leukocyte reaction (alloMLR) culture. Control human IgG1 (trastuzumab) and 3C12C mAbs were tested (0.125mg d-1) in a xenogeneic model of GVHD utilizing human PBMC transplanted into total body irradiation and anti-NK conditioned SCID mice. The genetically engineered hCD83 KI mouse was shown to be immune-competent and used to test the effect of 3C12C on LPS activated DC and T cells. Results: There were distinct CD83 splice variants (full length CD83, splicing variant CD83a, CD83b and CD83c) in different immune cells. CD83 glycosylation status also differed with high glycosylation required for surface expression on activated DC, whereas its expression on activated B cells and monocytes was resistant to de-glycosylation. Increases in CD83 expression on T cells occurred early with different kinetics, underlining the distinct signal pathway involved. The 3C12C mAb reduced T cell proliferation in the alloMLR but did not affect cytomegalovirus (CMV) or influenza (Flu) specific CD8+T cell numbers. Treatment with 3C12C prevented GVHD in human PBMC transplanted SCID mice, which otherwise developed histological GVHD between d8-13. Human DC were activated by d2 and expressed the CMRF-44 activation marker plus CD83, CD80 and CD86. Treatment with 3C12C mAb eliminated CD83+ CMRF44+ DC early post-transplant and reduced T cell activation. Further studies, established CMV and Flu specific T cells were retained and responded to antigen by IFNg production. Furthermore, Treg numbers were preserved. The 3C12C mAb depleted LPS activated DC in hCD83 KI mice in experiments performed prior to commencing transplant studies. Conclusion: These findings suggest that the potential therapeutic human anti-CD83 mAb induced significant immune suppression, by depletion of activated DC and consequential modulation of T cell activation. The reduction in allo/xeno activated T cells may result in part from a direct effect of anti-CD83 on early T cell responses. This apparently selective immunosuppressive effect preserves anti-viral T cell immunity and Treg pathways, suggesting that 3C12C merits further investigation as a novel agent for GVHD prophylaxis. Disclosures Hart: DendroCyte BioTech Pty Ltd: Equity Ownership. Clark:DendroCyte BioTech Pty Ltd: Equity Ownership.

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PI3K-Independent Signaling Pathways Contribute to ICOS-Mediated T-Cell Costimulation in Acute Graft-Versus-Host Disease in Mice.

Blood ◽

10.1182/blood.v120.21.3003.3003 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3003-3003

Author(s):

Jun Li ◽

Julie Leconte ◽

Kenrick Semple ◽

Jessica Heinrichs ◽

Claudio Anasetti ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Acute Gvhd ◽

Calcium Flux ◽

Pi3k Signaling ◽

Graft Versus Host ◽

Acute Graft

Abstract Abstract 3003 ICOS provides an important costimulation to promote T-cell activation and function. Using a knock-in mouse strain, termed ICOS-YF, in which the cytoplasmic tail of ICOS cannot activate phosphoinositide 3-kinase (PI3K), we have shown that ICOS-PI3K signaling axis is critical for the generation of follicular helper T cells. We also observed that, in both CD4+ and CD8+ T cells, ICOS could potentiate TCR-mediated calcium flux in a PI3K-independent manner in vitro. Although ICOS can potentiate TCR-mediated calcium flux independent of PI3K, its biological significance is unclear. To address this question, we studied the function of ICOS-YF T cells in comparison with ICOS wild-type (WT) and knock-out (KO) T cells in MHC-mismatched bone marrow transplantation (BMT) models. Severity of acute graft-versus-host disease (GVHD) was evaluated based on recipient survival, body weight change, and pathologic scores. Consistent with the data previously published by us and others, ICOS KO T cells had significantly reduced ability to cause acute GVHD as compared to WT T cells. We further observed that YF T cells were significantly more capable in causing GVHD than KO T cells, but less capable than WT T cells. Mechanically, the levels of serum TNFa and IFNg were similar in the recipients of YF or KO T cells, but significantly lower than those of WT T cells. However, on the per-cell basis, YF CD8+ T cells expressed similar levels of intracellular IFNg as WT T cells, but significantly higher than KO T cells. We further compared the ability of CD4+ or CD8+ T cells alone in the induction of acute GVHD, and found that CD4+ T cells from YF and KO mice were similarly impaired in their capacity to induce acute GVHD. In contrast, the pathogenic capacity of CD8+ T cells from YF mice was comparable to that of WT cells, whereas KO CD8+ T cells were significantly less pathogenic. These results suggest that although both CD4+ and CD8+ T cells depend on ICOS costimulation, the downstream signaling pathways they utilize are distinct: CD4+ T cells depend on ICOS-PI3K signaling whereas CD8+ T cells are more dependent on PI3K-independent pathways, probably calcium signaling. Taken together, our study reveals a complexity in ICOS signaling mechanisms in T cell activation and GVHD induction. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.1050.1050 ◽

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20201763 ◽

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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Role of Lymphotoxin α in T-Cell Responses during an Acute Viral Infection

Journal of Virology ◽

10.1128/jvi.76.8.3943-3951.2002 ◽

2002 ◽

Vol 76 (8) ◽

pp. 3943-3951 ◽

Cited By ~ 38

Author(s):

M. Suresh ◽

Gibson Lanier ◽

Mary Katherine Large ◽

Jason K. Whitmire ◽

John D. Altman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

T Cell Responses ◽

Cell Responses ◽

Lymphotoxin Α

ABSTRACT The importance of lymphotoxin α (LTα) in lymphoid organogenesis is well established. Although LTα has been implicated in the pathogenesis of T-cell-mediated immunopathologies, the requirement for LTα in T-cell activation and effector function in vivo is not well understood. To determine the role of LTα in T-cell activation in vivo, we compared the generation of antigen-specific T-cell responses between wild type (+/+) and LTα-deficient (LTα−/−) mice during an acute infection with lymphocytic choriomeningitis virus (LCMV). Our studies showed that LCMV-infected LTα−/− mice had a profound impairment in the activation and expansion of virus-specific CD8 T cells in the spleen, as determined by cytotoxicity assays, intracellular staining for gamma interferon, and staining with major histocompatibility complex class I tetramers. Further, the nonlymphoid organs of LTα−/− mice also contained substantially lower number of LCMV-specific CD8 T cells than those of +/+ mice. Greatly reduced virus-specific CD8 T-cell responses in LTα−/− mice led to a defect in LCMV clearance from the tissues. In comparison to that in +/+ mice, the activation of LCMV-specific CD4 T cells was also significantly attenuated in LTα−/− mice. Adoptive transfer experiments were conducted to determine if abnormal lymphoid architecture in LTα−/− mice caused the impairment in the activation of LCMV-specific T-cell responses. Upon adoptive transfer into +/+ mice, the activation and expansion of LCMV-specific LTα−/− T cells were restored to levels comparable to those of +/+ T cells. In a reciprocal cell transfer experiment, activation of +/+ T cells was significantly reduced upon transfer into LTα−/− mice. These results showed that impairment in the activation of LCMV-specific T cells in LTα−/− mice may be due to abnormal lymphoid architecture and not to an intrinsic defect in LTα−/− T cells.

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CD26 Blockade by Humanized Monoclonal Antibody Leads to Prophylaxis and Treatment of Graft-Versus-Host Disease (GVHD) in Hu-PBL-NOG Model Mice,

Blood ◽

10.1182/blood.v118.21.4018.4018 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4018-4018

Author(s):

Ryo Hatano ◽

Kei Ohnuma ◽

Taketo Yamada ◽

Takaaki Ooki ◽

Junpei Yamamoto ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Activation ◽

Human Lymphocytes ◽

Graft Versus Host ◽

Human T Cells

Abstract Abstract 4018 CD26 is a 110-kDa multifunctional membrane-bound glycoprotein with dipeptidyl peptidase IV (DPPIV) enzyme activity present on a wide variety of cells, and is critical in T cell biology, as a marker of T cell activation. The role of CD26 in immune regulation has been extensively characterized, with our recent findings elucidating its linkage with signaling pathways and structures involved in T cell activation as well as antigen presenting cell (APC)-T cell interaction. CD26 in human T cells has a costimulatory function and is upregulated after activation. On the other hand, in murine lymphocytes, CD26 is expressed in CD4-CD8- thymocytes and its expression level is not changed by various stimulation procedures. Moreover, murine T cells are not observed to be activated via CD26. Therefore, for the analysis of CD26-mediated immuneregulation leading to clinical applications, it is necessary to use a pathological model system caused by human T cells but not murine T cells. For this purpose, we used a xenogeneic graft-versus-host disease (x-GVHD) murine model, which is generated by transplantation of human T cells into NOG-Scid mice (hu-PBL-NOG). In this model mouse, x-GVHD is developed by manifesting rough hair, loss of weight and motility, since transplanted human T cells become effector cells in murine organs. By examining the cytotoxic functions of human CD8+ T cells after CD26-mediated costimulation in vitro, we have shown that CD26-mediated costimulation induced vigorous secretion of inflammatory cytokines, TNF-a, IFN-g and soluble Fas Ligand, and strongly enhanced the expression of Granzyme B. These results suggested that cytotoxic function in human CD8+ T cells activated via CD26-mediated costimulation has a key role in developing x-GVHD. In the present study, we showed that CD26 blockade by humanized anti-CD26 monoclonal antibody (huCD26mAb) reduced development of x-GVHD, and that this effect of CD26 blockade was exerted by suppression of cytotoxic activity of human CD8+ T cells in vivo. Moreover, huCD26mAb showed as same effect on suppression of x-GVHD as clinically available drug, abatacept (CTLA4-Ig), a blockade of CD28-mediated costimulation. While increased dose of CTLA4-Ig showed more suppressive effect on x-GVHD but sustained suppression of engraftment of transplanted human T cells, the same dose of huCD26mAb showed no delay in engraftment. We performed a further analysis of peripheral human lymphocytes in hu-PBL-NOG after administration of huCD26mAb or CTLA4-Ig. Although CD26 expression on both human CD4+ T cells and CD8+ T cells was markedly increased in control mice with human IgG administration as compared with those before transplantation, the engraftment of human CD26+ T cells was completely inhibited in huCD26mAb administered hu-PBL-NOG. As a result of analysis of human T cells engrafted in spleen of NOG-Scid mice transplanted with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled human lymphocytes, huCD26mAb administration preferentially suppressed the priming of human CD8+ T cells rather than CD4+ T cells, while CTLA4-Ig strongly suppressed the cell division of both human CD4+ T cells and CD8+ T cells. Our data strongly suggested that CD26-mediated costimulatory activation in human CD8+ T cells was deeply involved in the pathogenesis of x-GVHD, and blocking the CD26-mediated costimulation resulted in prophylaxis and treatment of x-GVHD. Taken together, our results support the notion that CD26 blockade by huCD26mAb may become a promising therapeutic strategy for GVHD and other refractory immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.

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CD8+ T Cells in Atherosclerosis

Cells ◽

10.3390/cells10010037 ◽

2020 ◽

Vol 10 (1) ◽

pp. 37

Author(s):

Sarah Schäfer ◽

Alma Zernecke

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Critical Role ◽

Cd8 T Cell ◽

Immune Checkpoints ◽

Cell Functions

Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8+ T cells. The CD8+ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8+ T cells ameliorates atherosclerosis. CD8+ T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8+ T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8+ T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8+ T cells and their cytotoxic activity. CD8+ T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25+CD8+ T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8+ T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8+ T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8+ T cells in atherosclerosis.

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Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

Science Immunology ◽

10.1126/sciimmunol.abf7570 ◽

2021 ◽

Vol 6 (57) ◽

pp. eabf7570

Author(s):

Laura A. Vella ◽

Josephine R. Giles ◽

Amy E. Baxter ◽

Derek A. Oldridge ◽

Caroline Diorio ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Immune Activation ◽

Cell Activation ◽

Vascular Complications ◽

Adult Disease ◽

Vasoactive Medication ◽

Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

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