CD5-CK2 Binding/Activation-Deficient Mice Are Resistant to Experimental Autoimmune Encephalomyelitis: Protection Is Associated with Diminished Populations of IL-17-Expressing T Cells in the Central Nervous System

Axtell, Robert C.; Xu, Liang; Barnum, Scott R.; Raman, Chander

doi:10.4049/jimmunol.177.12.8542

Cited by 87 publications

(94 citation statements)

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“…More specifically, Casein Kinase 2, a serine/threonine kinase that associates with CD5 in thymocytes [37], was shown to play a crucial role in cell survival and apoptosis [61]. In this context, CD5 À/À CD4 1 T cells, as well as CD4 1 T lymphocytes that express a Casein Kinase 2 binding/ activation-deficient CD5, are more susceptible to apoptosis induction than WT CD4 1 T cells [62]. However, the molecular mechanism by which CD5 may prevent thymocyte apoptosis had not yet been explored.…”

Section: Discussionmentioning

confidence: 99%

“…For suppression assays, CD4 1 CD25 1/hi (Treg) and CD4 1 CD25 À naïve T cells (T effectors, Teff) (1 Â 10 5 ) were incubated at 1:1 ratio in the presence of irradiated splenocytes and stimulated with anti-CD3 antibody. T-cell proliferation was measured by 3 activation-deficient CD5, are more susceptible to apoptosis induction than WT CD4 1 T cells [62]. However, the molecular mechanism by which CD5 may prevent thymocyte apoptosis had not yet been explored.…”

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Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

et al. 2009

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It has been suggested that high affinity/avidity interactions are required for the thymic selection of Treg. Here, we investigated the role of CD5, a negative regulator of TCR signaling, in the selection and function of ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg). Analysis of CD5 À/À mice showed a significant increase in the percentage and absolute numbers of CD4 1 CD25 1 Foxp3 1 thymocytes and peripheral T lymphocytes, compared with BALB/c mice. Thymi from CD5 À/À mice showed reduced cellularity due to increased apoptosis, which preferentially affected naïve T cells. To characterize nTreg selection at the molecular level we investigated the phosphorylation of Erk, c-Cbl, PI3K and Akt. CD5 À/À nTreg showed increased basal levels of p-Erk compared with wild-type nTreg. Interestingly, in response to CD3 plus CD28 costimulation, CD5 À/À naïve T cells but not CD5 À/À nTreg showed lower levels of p-Akt. Finally, CD5 À/À nTreg were thymus-derived and fully functional. We conclude that the enrichment of nTreg observed in the absence of CD5 signaling is due to de novo generation of nTreg and selective reduction of CD4 1 CD25 À naïve thymocytes. Furthermore, we provide new evidence supporting a potential role of CD5 in thymocyte survival, through a mechanism that may involve the phosphorylation of Akt.Key words: CD5 . Development . Treg . Signaling . Thymocyte IntroductionThe maintenance of immunological self-tolerance is a fundamental property of the immune system besides the clearance of pathogenic agents. Central and peripheral mechanisms exist to ensure the elimination or inactivation of potentially harmful autoreactive T cells. Negative selection in the thymus induces the deletion of most self-reactive T-cell clones during T-cell development [1]. However, some autoreactive T cells escape from clonal deletion and need to be controlled by peripheral mechanisms including peripheral T-cell deletion by activation-induced cell death [2], T-cell anergy [3] and T-cell-mediated suppression [4].Recently, non-deletional mechanisms of central tolerance have been re-evaluated, such as the development of thymus-derived Treg [5]. These cells are currently known as ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg), which represent a small population (5-10%) of peripheral CD4 1 T cells and are characterized by high levels of surface CD25 and by the expression of Foxp3, a transcription factor, identified as a key regulator of nTreg development and function [6]. In addition, nTreg also express activation markers such 2233as CTLA-4, glucocorticoid-induced tumor necrosis factor receptor (GITR), CD62L, OX40 and CD103 [7,8]. nTreg were first studied for their role in maintaining self-tolerance [9], preventing autoimmune diseases [10] and the development of harmful immunopathological responses [11]. However, nTreg can also participate in modulating adaptive immunity to viruses, bacteria and parasites affecting favorably or detrimentally the outcome of immune responses to infections [12,13].The mechanisms of suppression used by Treg...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

et al. 2009

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“…Interestingly, it has been shown that EAE is also more difficult to induce in transgenic mice that express a CD5 molecule deficient in its interaction with casein kinase 2 (48,49). The increased resistance to EAE has been interpreted to be due to reduced survival of effector T cells in these mice.…”

Section: Discussionmentioning

confidence: 99%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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A subset of CD4 + T cells, the CD4 + CD25 + T reg cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T reg ) cells' and for activation of the effector function of CD4 + CD25 + regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that T reg cells obtained from CD5 −/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 + CD25 − responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on T reg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5 −/− T reg thymocytes were able to elicit a higher Ca 2+ response to TCR + co-stimulatory signals than the wild type cells. CD5 −/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the DSS-induced colitis in CD5 −/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4 + CD25 + T reg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders.

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“…High levels of CD5 are associated with resistance to activation in peripheral T cells and blocking CD5 restores their responsiveness (22). The negative regulatory ability of CD5 has also been shown to play a critical role in preventing hyper-proliferation and activation-induced cell death (AICD) when examining CD8 + T cells in a tumor model and in CD4 + and CD8 + cells in experimental autoimmune encephalomyelitis (23)(24)(25). We find that CD5 does prevent hyperproliferation in LLO56 and possibly AICD at later stages.…”

Section: Discussionmentioning

confidence: 99%

Distinct CD4 ⁺ helper T cells involved in primary and secondary responses to infection

Weber

Persaud

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

114

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Helper T cells are critical for protective immunity, CD8 + T-cell memory, and CD4 + recall responses, but whether the same or distinct CD4 + T cells are involved in these responses has not been established. Here we describe two CD4 + T cells, LLO118 and LLO56, specific for an immunodominant Listeria monocytogenes epitope, with dramatically different responses to primary and secondary infection. Comparing in vivo responses, LLO118 T cells proliferate more strongly to primary infection, whereas surprisingly, LLO56 has a superior CD4 + recall response to secondary infection. LLO118 T cells provide more robust help for CD8 + T-cell responses to secondary infection than LLO56. We found no detectable differences in antigen sensitivity, but naive LLO118 T cells have much lower levels of CD5 and their T-cell receptor levels are dramatically down-regulated after their strong primary response. Thus, distinct CD4 + helper T cells are specialized to help either in primary or secondary responses to infection.infectious disease | affinity | T-cell receptor transgenic mice | apoptosis C D4 + T cells are essential for CD8 + memory-cell formation, recall responses, and protective immunity (1-3). Despite the importance of CD4 + T cells in immune responses, studies examining T-cell responses to Listeria monocytogenes have focused primarily on CD8 + T cells (4). CD4 + T cells are not required for the primary CD8 + response to L. monocytogenes, but they play a critical role in the maintenance and survival of CD8 + memory cells (1-5). Memory cell formation is a hallmark of the adaptive immune system and successful memory cells must navigate expansion, contraction, and maintenance (6). Much more has been learned about the pathways for formation of CD8 + memory cells than CD4 + memory cells, but it is clear that the pathways for CD4 + memory formation are distinct (6-8). The parameters of optimal CD4 + help for CD8 + and CD4 + memory formation have not been characterized and represent an opportunity to effectively improve vaccines (9).T cells with shortened exposure to antigen do not successfully differentiate to memory cells (10). In contrast, overstimulation in a situation like chronic infection leads to T-cell exhaustion and ineffective memory cell formation or persistence (11). Thus, there appears to be a "goldilocks" level of T-cell stimulation for effective memory cell formation (6). Differences in the duration or abundance of antigen presentation or costimulatory molecules alter activation levels and T-cell receptor (TCR) levels and regulators on the T cell itself affect activation levels (12). TCR affinity and thymic development can also alter T-cell antigen sensitivity (13). For example, the surface expression of one Tcell-negative regulator of T-cell activation, CD5, correlates with the affinity of that developing TCR for self peptide (14-16). The relationship between effective CD4 + responses and the avidity of the TCR:pMHC interaction is not established and a polyclonal CD4 + T-cell population is not amenable to address the...

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CD5-CK2 Binding/Activation-Deficient Mice Are Resistant to Experimental Autoimmune Encephalomyelitis: Protection Is Associated with Diminished Populations of IL-17-Expressing T Cells in the Central Nervous System

Cited by 87 publications

References 51 publications

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

Distinct CD4 ⁺ helper T cells involved in primary and secondary responses to infection

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CD5-CK2 Binding/Activation-Deficient Mice Are Resistant to Experimental Autoimmune Encephalomyelitis: Protection Is Associated with Diminished Populations of IL-17-Expressing T Cells in the Central Nervous System

Cited by 87 publications

References 51 publications

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

Distinct CD4 + helper T cells involved in primary and secondary responses to infection

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Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Distinct CD4 ⁺ helper T cells involved in primary and secondary responses to infection