CD4+ICOS+ T lymphocytes inhibit T cell activation ‘in vitro’ and attenuate autoimmune encephalitis ‘in vivo’

Abstract

The inducible co-stimulator (ICOS, CD278) is essential to the efficient development of normal and pathological immune reactions. Since ICOS-deficient mice have enhanced susceptibility to experimental allergic encephalomyelitis (EAE), we have functionally analyzed a CD4+ICOS+ population comprising 6-15% of all CD4+ T cells in secondary lymphoid organs of unmanipulated wild-type mice and checked for their ability to suppress EAE. In C57BL/6 mice, CD4+ICOS+ cells were a major source of cytokines including IFN-gamma, IL-2, IL-4, IL-10 or IL-17A. Upon activation, these cells showed preferentially enhanced production of IL-4 or IL-10 but inhibited IFN-gamma production. In contrast, CD4+ICOS- cells mainly produced IFN-gamma. Interestingly, CD4+ICOS+ cells partially suppressed the proliferation of CD4+ICOS- or CD4+CD25- lymphocytes 'in vitro' by an IL-10-dependent mechanism. Furthermore, CD4+ICOS+ activated and expanded under appropriate conditions yielded a population enriched in cells producing IL-10 and T(h)2 cytokines that also suppressed the proliferation of CD4+CD25- lymphocytes. CD4+ICOS+ cells, before or after expansion in vitro, reduced the severity of EAE when transferred to ICOS-deficient mice. In the same EAE model, lymph node cells from ICOS-deficient mice receiving ICOS+ cells showed reduced IL-17A production and enhanced IL-10 secretion upon antigen activation in vitro. Thus, naturally occurring CD4+ICOS+ cells, expanded or not in vitro, are functionally relevant cells able of protecting ICOS-deficient mice from severe EAE.

Dual Control of Antitumor CD8 T Cells through the Programmed Death-1/Programmed Death-Ligand 1 Pathway and Immunosuppressive CD4 T Cells: Regulation and Counterregulation

“…ICOS is expressed on activated T cells, including CD4 and CD8 T cells (26), as well as regulatory T cells (31). ICOS on CD4 T cells has been linked to a Th2 phenotype (3, 40 -42), but also with IL-10 production (31,32,40,41,43) and with more suppressive regulatory T cells (31,44). Moreover, ICOS ϩ CD4 T cells were recently shown to control autoimmune responses (31,40), and ICOS is expressed on tumor-infiltrating regulatory T cells (31,44).…”

Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis

“…Prophylactic and therapeutic vaccination was performed in female C57BL/6 mice with EAE induced as previously described [27]. Mice (4-8 weeks old) were vaccinated by s.c. injection of PLGA-NP loaded with either 2 g MOG or mouse IL-10.…”

Suppression of CD4+T Lymphocyte Activationin Vitroand Experimental Encephalomyelitisin Vivoby the Phosphatidyl Inositol 3-Kinase Inhibitor PIK-75

“…The Disease Index was calculated by adding all the daily average disease scores; the result was divided by the average day of disease onset of each group and multiplied by 100. Other disease parameters were defined as described (16), as follows: The Day of Disease Onset was calculated by averaging the first day of clinical signs for each mouse in one experimental group. Maximum Disease Score was determined by averaging the highest score achieved by each individual mouse.…”