Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.

While CD28 is critical for expansion of naive T cells, recent evidence suggests that the activation of effector T cells is largely independent of CD28/B7. We suggest that ICOS, the third member of the CD28/CTLA-4 family, plays an important role in production of IL-2, IL-4, IL-5, and IFNgamma from recently activated T cells and contributes to T cell-dependent B help in vivo. Inhibition of ICOS attenuates lung mucosal inflammation induced by Th2 but not Th1 effector populations. Our data indicate a critical function for the third member of the CD28 family in T cell-dependent immune responses.

[SLAM]) is the prototypical member of a growing family of glycoprotein receptors on hematopoietic cells, which includes CD229, CD84, CD244, SF2000/Ly108, SF2001, and 19A(CRACC). [1][2][3][4][5][6][7][8] This "SLAM family" is defined by close sequence homology of the receptors that have one or more cytoplasmic tyrosine motifs with the consensus sequence Thr-(Ile/Val)-pTyr-x-x-Val. [9][10][11] The other members of the family, which do not have cytoplasmic tails (CD48, BCM1-like), are likely to act as ligands, as demonstrated for CD48 that is attached to the membrane by a lipid anchor. The cytoplasmic tyrosine motifs function as docking sites for the small cytoplasmic signaling molecules SLAM-associated protein (SAP, SH2D1A) and EWS/FLI1 activated transcript 2 (EAT). [12][13][14][15] In humans, CD150 is expressed on memory/activated T cells and strongly expressed on T H 1 helper T cells, B cells, thymocytes, and dendritic cells. [16][17][18][19][20][21][22][23][24] CD150 is a self-ligand 25,26 thought to play an important role in adhesion and signaling in the immune synapse between the T cell and antigen-presenting cell (APC). Two major immune functions have been ascribed to CD150 in in vitro human studies, costimulation of T-cell proliferation and augmentation of the interferon ␥ (IFN-␥) response. 18 Many T-cell surface receptors have been shown to function to various degrees as costimulation molecules in that they induce enhanced proliferation during T-cell receptor (TCR) engagement. Examples of these costimulation receptor/ligand pairs include CD28/B7.1/B7.2, ICOS/B7RP1, LFA1/ ICAM, 4-1BB/4-1BBL, OX40/OX40L, and CD27/CD70. 27-32 Unlike the archetypal costimulatory pair CD28/B7, many of these receptor pairs are induced on activation; thus, costimulatory function follows shortly after the initial TCR triggering event.Although CD150 is in this inducible category of receptors, it is different in 2 respects. First, CD150 signals through interaction with SAP in T cells and EAT in APCs. These small (128 amino acids) molecules, which comprise an SH2 domain with a short tail, are structurally similar but differ subtly in their binding characteristics to the SLAM family receptors. 14 Second, CD150 is strongly expressed on the surface of established T H 1 cells and monoclonal antibodies directed at CD150 augment IFN-␥ production following TCR triggering in human T cells. Thus, CD150 has 2 major roles in T-cell activation-costimulation and control of IFN-␥ production.SAP is likely a pivotal signaling molecule for the 6 members of the SLAM family of receptors. This is becoming clear through studies on patients with mutations of the SAP gene sh2d1a, which result in the fatal X-linked lymphoproliferative disease (XLP), familial hemophagocytic lymphohistiocytosis (FHL), and combined variable immunodeficiency (CVID), [33][34][35][36][37] and through studies performed with the SAP Ϫ/Ϫ mouse. 34 For personal use only. on May 12, 2018. by guest www.bloodjournal.org From infectious mononucleosis, B-cell lymphomas, and dysgammaglob...