T cell activation is regulated by the innate immune system through positive and negative costimulatory molecules. B7-H3 is a novel B7-like molecule with a putative receptor on activated T cells. Human B7-H3 was first described as a positive costimulator, most potently inducing IFN-γ production and cellular immunity. In this study we examined the expression and function of mouse B7-H3. B7-H3 is mostly expressed on professional APCs; its expression on dendritic cells appears to be up-regulated by LPS. In contrast to human B7-H3, we found that mouse B7-H3 protein inhibited T cell activation and effector cytokine production. An antagonistic mAb to B7-H3 enhanced T cell proliferation in vitro and led to exacerbated experimental autoimmune encephalomyelitis in vivo. Therefore, mouse B7-H3 serves as a negative regulator of T cell activation and function.

Mitogen-activated protein (MAP) kinases are essential regulators in immune responses, and their activities are modulated by kinases and phosphatases. MAP kinase phosphatase (MKP) is a family of dual-specificity phosphatases whose function is evolutionarily conserved. A number of mammalian MKPs have been identified so far, but their specific physiological functions in negative regulation of MAP kinases have not been genetically defined. Here we examine innate and adaptive immune responses in the absence of MKP5. JNK activity was selectively increased in Mkp5 (also known as Dusp10)-deficient mouse cells. Mkp5-deficient cells produced greatly enhanced levels of pro-inflammatory cytokines during innate immune responses and exhibited greater T-cell activation than their wild-type counterparts. However, Mkp5-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, Mkp5-deficient CD4(+) and CD8(+) effector T cells produced significantly increased levels of cytokines compared with wild-type cells, which led to much more robust and rapidly fatal immune responses to secondary infection with lymphocytic choriomeningitis virus. Therefore, MKP5 has a principal function in both innate and adaptive immune responses, and represents a novel target for therapeutic intervention of immune diseases.

Helper T (Th) cell differentiation is accompanied by complex transcriptional changes. Although costimulatory receptors are important in Th differentiation, the underlying mechanisms are poorly understood. Here we examine the transcriptional mechanisms by which ICOS regulates Th2 differentiation and selective IL-4 expression by effector T cells. We found impaired expression of c-Maf transcription factor functionally associated with the IL-4 defect in ICOS(-/-) cells. c-Maf expression in effector cells was regulated by IL-4 levels during Th differentiation. ICOS costimulation potentiated the T cell receptor (TcR)-mediated initial IL-4 production, possibly through the enhancement of NFATc1 expression. These data indicate that ICOS, by enhancing TcR signals at an early stage of T cell activation, regulates IL-4 transcription and T cell function in effector cells.

Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: rheumatoid arthritis (RA); collagen-induced arthritis (CIA); chicken type II collagen (CII); inducible costimulator (ICOS); prostaglandin E2 (PGE2).