Cutting Edge: The SLAM Family Receptor Ly108 Controls T Cell and Neutrophil Functions

Abstract

Ly108, a glycoprotein of the signaling lymphocytic activation molecule family of cell surface receptors expressed by T, B, NK, and APCs has been shown to have a role in NK cell cytotoxicity and T cell cytokine responses. In this study, we describe that CD4+ T cells from mice with a targeted disruption of exons 2 and 3 of Ly108 (Ly108ΔE2+3) produce significantly less IL-4 than wild-type CD4+ cells, as judged by in vitro assays and by in vivo responses to cutaneous infection with Leishmania mexicana. Surprisingly, neutrophil functions are controlled by Ly108. Ly108ΔE2+3 mice are highly susceptible to infection with Salmonella typhimurium, bactericidal activity of Ly108ΔE2+3 neutrophils is defective, and their production of IL-6, IL-12, and TNF-α is increased. The aberrant bactericidal activity by Ly108ΔE2+3 neutrophils is a consequence of severely reduced production of reactive oxygen species following phagocytosis of bacteria. Thus, Ly108 serves as a regulator of both innate and adaptive immune responses.

Prevalence and evolutionary origins of autoimmune susceptibility alleles in natural mouse populations

“…In particular, the measles virus, the canine distemper virus and rinderpest virus all bind Cd150. 31 Targeted deletions of Ly108 and Cd150 have each been shown to impact infection with Leishmania in mice, 32,33 consistent with the notion that functional polymorphisms of these molecules may modulate susceptibility to infectious diseases.…”

“…34,35 Several investigations have associated changes in cytokine secretion with disruptions of genes in the SLAM/CD2 family. 32 In addition, SAP (SLAM-associated protein or SH2D1A), which acts directly downstream of this family, plays a role in Th2 regulation and cytokine production. 36,37 Mutations in SAP have been linked to dysregulations in viral immunity, including X-linked lymphoproliferative syndrome, which is caused by an inappropriate response to Epstein-Barr Virus (EBV) infection.…”

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

“…It is activated by tyrosine phosphorylation and is required for T cell antigen receptor-induced cytoskeletal reorganization, proliferation, and effector functions. These activities can easily explain the stimulatory impact of anti-Ly108 antibodies on antigen receptor-induced T cell cytokine secretion in normal CD4 ϩ T cells and the defect in T H 2 cytokine secretion observed in Ly108-deficient CD4 ϩ T cells (15,16). They probably also underlie the greater TCR-triggered calcium signals seen in T cells preferentially expressing Ly108-1 over Ly108-2 (2).…”

“…These observations suggested that Ly108 may be implicated in the pathophysiology of autoimmune diseases by regulating T H 1 cytokine production by CD4 ϩ T cells. Paradoxically, analyses of T cells from mice engineered to lack most of the extracellular domain of Ly108 (ly108 ⌬E2 ϩ 3 ) suggested that Ly108 played a role in T helper 2 (T H 2) cytokine production (16). Although the basis for these contradictory results remains to be established, these data nonetheless offered a compelling indication that Ly108 participates in normal immunity and autoimmune pathologies.…”

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

“…Mutations in SH2D1A, the gene encoding SAP, are responsible for the primary immunodeficiency X-linked lymphoproliferative disease (XLP) in humans [10][11][12]. Studies using knock-out mice deficient in SAP and SLAM family receptors indicate that SLAM family receptors and SAP play an important role in T cell-mediated help for humoral immunity [13][14][15][16].…”