Signaling lymphocyte activation molecule (SLAM), a glycoprotein expressed on activated lymphocytes and antigen-presenting cells, has been shown to be a coregulator of antigen-driven T cell responses and is one of the two receptors for measles virus. Here we show that T cell receptor–induced interleukin (IL)-4 secretion by SLAM^−/− CD4⁺ cells is down-regulated, whereas interferon γ production by CD4⁺ T cells is only slightly up-regulated. Although SLAM controls production of IL-12, tumor necrosis factor, and nitric oxide in response to lipopolysaccharide (LPS) by macrophages, SLAM does not regulate phagocytosis and responses to peptidoglycan or CpG. Thus, SLAM acts as a coreceptor that regulates signals transduced by the major LPS receptor Toll-like receptor 4 on the surface of mouse macrophages. A defective macrophage function resulted in an inability of SLAM^−/− C57Bl/6 mice to remove the parasite Leishmania major. We conclude that the coreceptor SLAM plays a central role at the interface of acquired and innate immune responses.

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that inSH2D1A^-/-mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent inSH2D1A^-/-mice upon primary immunization, and because SH2D1A was detectable inwtgerminal center B cells, we examined whetherSH2D1A^-/-B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primedSH2D1A^-/-mice with CD4⁺T cells from primedwtmice into irradiatedwtmice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naïveSH2D1A^-/-B cells became evident upon cotransfer with non-primedwtCD4⁺cells intoRag2^-/-recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.

Slamf8 (CD353) is a cell surface receptor that is expressed upon activation of macrophages (MΦs) by IFN-γ or bacteria. In this article, we report that a very high NADPH oxidase (Nox2) enzyme activity was found in Slamf8^−/− MΦs in response to Escherichia coli or Staphylococcus aureus, as well as to PMA. The elevated Nox2 activity in Slamf8^−/− MΦs was also demonstrated in E. coli or S. aureus phagosomes by using a pH indicator system and was further confirmed by a reduction in the enzyme activity after transfection of the receptor into Slamf8-deficient primary MΦs or RAW 264.7 cells. Upon exposure to bacteria or PMA, protein kinase C activity in Slamf8^−/− MΦs is increased. This results in an enhanced phosphorylation of p40phox, one key component of the Nox2 enzyme complex, which, in turn, leads to greater Nox2 activity. Taken together, the data show that, in response to inflammation-associated stimuli, the inducible receptor Slamf8 negatively regulates inflammatory responses.

Several autoimmune disease models depend on an imbalance in the activation of aggressor T_h1 and CD4⁺CD25⁺ regulatory T (T_reg) cells. Here we compare the requirement for signals through the co‐stimulatory molecules CD28 and inducible co‐stimulator (ICOS) in chronic murine colitis, a model for inflammatory bowel disease. We used a colitis model in which disease‐causing CD45RB^hi T cells alone or in combination with CD4⁺CD25⁺ T cells from either CD28‐deficient or wild‐type donors were transferred into T cell‐deficient animals, half of which were treated with ICOS‐blocking reagents. Blocking ICOS on the surface of CD28‐deficient T_h1 cells abrogated development of colitis, whereas blocking CD28 or ICOS alone had little to no effect on disease induction. In contrast to T_h1 cells, regulatory T cell functioning depended mostly on CD28 signaling with only a minor contribution for ICOS. We conclude that CD28 and ICOS collaborate to development of murine colitis by aggressor T_h1 cells, and that CD28 is required for T_reg cells, which should caution against the use of CD28‐blocking reagents in inflammatory bowel disease.