Altered Proliferative Response by T Lymphocytes of Ly-6A (Sca-1) Null Mice

Abstract

Ly-6A is a murine antigen which is implicated in lymphocyte activation and may be involved in activation of hematopoietic stem cells. Antibody cross-linking studies and antisense experiments have suggested that Ly-6A is a lymphocyte coactivation molecule. To better understand the function of Ly-6A, we used gene targeting to produce Ly-6A null mice which are healthy and have normal numbers and percentages of hematopoietic lineages. However, T lymphocytes from Ly-6A–deficient animals proliferate at a significantly higher rate in response to antigens and mitogens than wild-type littermates. In addition, Ly-6A mutant splenocytes generate more cytotoxic T lymphocytes compared to wild-type splenocytes when cocultured with alloantigen. This enhanced proliferation is not due to alterations in kinetics of response, sensitivity to stimulant concentration, or cytokine production by the T cell population, and is manifest in both in vivo and in vitro T cell responses. Moreover, T cells from Ly-6A–deficient animals exhibit a prolonged proliferative response to antigen stimulation, thereby suggesting that Ly-6A acts to downmodulate lymphocyte responses.

A Monoclonal Antibody Against the 66-kDa Protein Expressed in Mouse Spleen and Thymus Inhibits Ly-6A.2-Dependent Cell-Cell Adhesion

“…These previously published observations indicate that expression of Ly-6A.2 is critical for activation through the Ag receptor. Contrary to the above studies, CD4 ϩ T cells from Ly-6A mutant mice are modestly hyper-responsive to anti-CD3 Ab compared with their wild-type littermates (37). In addition, T cells from Ly-6A.2-null mice have a prolonged proliferative response to Ag stimulation.…”

Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation

“…32 Particularly interesting possibilities arise from the phenotype of mice lacking Ly-6A, T cells of which exhibit prolonged proliferative responses to antigen stimulation. 33 This suggests a down-regulatory function of Ly-6A. If a similar role for Ly-6G is hypothesized then it is tempting to imagine that antibody ligation of Ly-6G might remove an important negative regulator of neutrophil function, resulting in activation and the responses we have described.…”

Ly-6I, a New Member of the Murine Ly-6 Superfamily with a Distinct Pattern of Expression

“…Studies of Ly-6A/E knockout mice (24) and disruption of the Ly-6C gene in NOD mice have revealed no function for these molecules in hemopoiesis. One explanation for these results is that some of the Ly-6SF members are functionally redundant, so that the loss of one gene is not sufficient to affect lymphoid cell development.…”

“…Gene knockouts have only been analyzed for Ly-6A/E, which suggested that the Ag may have an inhibitory role in regulating cell activation (24). Other studies have suggested roles in cell adhesion in lymphocytes (25) and bone marrow stroma (26) and in T cell Ag-specific immune responses (27).…”