CD8⁺T cells control the TH phenotype of MBP-reactive CD4⁺T cells in EAE mice

Abstract

T o regulate the immune response and dampen the potential for autoimmunity, the immune system has evolved several mechanisms to down-regulate and control the outgrowth and differentiation of activated CD4 ϩ T cells. One level of control, mediated during the initial interaction of the CD4 ϩ T cell with MHC͞peptide complexes on the surface of antigen-presenting cells, determines whether T cell activation, anergy, or apoptosis will ensue (1-3). A second level of control, mediated by cytokines, regulates the growth and differentiation of activated CD4 ϩ T cells. Different cytokines secreted by CD4 ϩ or CD8 ϩ T cells either stimulate or inhibit CD4 ϩ T cell proliferation and determine whether a naïve T helper (TH) precursor cell differentiates as an IFN-␥-producing TH1 cell or as an IL-4-and IL-10-producing TH2 cell (4-6). A third level of control resides in the regulatory T cells including both CD4 ϩ (7) and CD8 ϩ (8) T cell populations. For example, ample data demonstrate the ability of CD8 ϩ T cells to regulate CD4 ϩ T cell responses (9-13). These effects of CD8 ϩ T cells have been mostly attributed, in recent years, to the CD8 ϩ T cells' secretion of cytokines (14).In addition to identifying cytokines as potential effectors of immune regulation by CD8 ϩ T cells, other studies have identified specific cognate interactions between regulatory CD8 ϩ T cells and activated CD4 ϩ T cells. For example, during antigen-or superantigen-driven CD4 ϩ T cell responses in vivo, CD8 ϩ T cells emerge that specifically regulate CD4 ϩ T cells in a T cell antigen receptor (TCR) V␤-specific manner (15, 16). These CD8 ϩ T cells preferentially recognize antigen-activated CD4 ϩ T cell clones expressing certain TCR V␤ molecules and are restricted by the class I-b MHC molecule Qa-1. Unlike conventional MHC class I-a molecules, Qa-1 molecules are expressed only at low levels on resting T cells but are increased after antigen activation (17). These data are consistent with a model of specific immunoregulation in which after antigen activation CD4 ϩ T cells express membrane Qa-1͞TCRV␤ motifs that are recognized by the ␣␤ TCR expressed by precursor regulatory CD8 ϩ T cells. These CD8 ϩ T cells are induced to differentiate and down-regulate CD4 ϩ T cells expressing the particular Qa-1͞TCRV␤ motifs.A prediction of this model is that Qa-1-restricted, V␤-specific regulatory CD8 ϩ T cells will be induced by ''vaccination'' of animals with antigen-activated CD4 ϩ T cells, using T cell vaccination (TCV) protocols known to prevent autoimmune disease in animal models (18,19). In this regard, we have shown that Qa-1-restricted, V␤-specific CD8 ϩ cytotoxic T cell lines are induced by TCV (16). Moreover, we isolated a CD8 ϩ T hybridoma clone from a T cell-vaccinated mouse that preferentially recognizes CD4 ϩ V␤8 ϩ but not CD4 ϩ V␤6 ϩ myelin basic protein (MBP)-reactive clones in a Qa-1-restricted fashion (16). In this current study, we further confirmed this prediction by investigating an experimental autoimmune encephalomyelitis (EAE) model system in wh...

Expression of the Long Form of Human FLIP by Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates Experimental Autoimmune Encephalomyelitis

“…A consequence using our approach was that overexpression of hFLIP L in the immune system probably also encompassed cells with immunoregulatory properties such as CD25 ϩ CD4 ϩ T cells (15), CD8 ϩ T cells (16), dendritic cells (18), NK cells (19), and NK T cells (17). Despite this widespread expression of hFLIP L , the disease course was still aggravated.…”

“…Suppression of autoimmune CD4 ϩ T cells by regulatory cells may be another component of the disease-limiting process (15)(16)(17)(18)(19). Furthermore, deletion of encephalitogenic T cells through activation-induced cell death (AICD) has also been proposed to contribute to the resolution of inflammation (20 -22).…”

CD8+ T cells control corneal disease following ocular infection with herpes simplex virus type 1

“…While most of the recent literature has focused on CD4 + CD25 + T cells with regulatory activity (Field et al, 2001;Piccirillo & Shevach, 2001;Skelsey et al, 2003), there also exist CD8 + T cells that express regulatory functions (Cosmi et al, 2003;Ferguson et al, 2002Ferguson et al, , 2003. These CD8 + T regulatory cells are found in both humans (Cortesini et al, 2002;Filaci & Suciu-Foca, 2002) and mice (Ferguson et al, 2002;Jiang & Chess, 2000;Jiang et al, 2001) and operate in a variety of antigen-specific responses (Ferguson et al, 2002;Nakamura et al, 2003) and diseases (Jiang et al, 2001;Taneja et al, 2002;Zhang et al, 2002). They have also been implicated in viral and parasitic infections (Hafalla et al, 2003).…”

CD8+T cells are not necessary for 1α,25-dihydroxyvitamin D3to suppress experimental autoimmune encephalomyelitis in mice

“…In addition, beneficial effects of CD8 ϩ T cells have been reported in studies where feeding of myelin antigens leads to the generation of CD8 ϩ T cells that suppress EAE induction (30). There have been reports of isolation of a CD8 ϩ T cell suppressor cell line that reduces EAE severity in mice and rats by targeting and destroying CD4 ϩ effector cells (31,32).Because activated CD8 ϩ T cells have high levels of VDR and have been implicated as effectors or suppressors of EAE, we decided to investigate whether 1,25-(OH) 2 D 3 prevents EAE induction through a mechanism involving CD8 ϩ T cells. To do Abbreviations: 1,25-(OH)2D3, 1,25-dihydroxyvitamin D3; EAE, experimental autoimmune encephalomyelitis; VDR, vitamin D receptor; MS, multiple sclerosis; MBP, myelin basic protein.…”

“…In addition, beneficial effects of CD8 ϩ T cells have been reported in studies where feeding of myelin antigens leads to the generation of CD8 ϩ T cells that suppress EAE induction (30). There have been reports of isolation of a CD8 ϩ T cell suppressor cell line that reduces EAE severity in mice and rats by targeting and destroying CD4 ϩ effector cells (31,32).…”