The Tetraspanin CD37 Orchestrates the α 4 β 1 Integrin–Akt Signaling Axis and Supports Long-Lived Plasma Cell Survival

Antibody-producing B cells require CD37-dependent integrin signaling for long-term survival. To generate immunological memory, B cells with high-affinity immunoglobulin receptors proliferate and differentiate in germinal centers in the spleen to produce memory B cells and long-lived antibody-secreting cells known as plasma cells. van Spriel et al . found that mice deficient in the tetraspanin protein CD37 had defective antibody production and decreased numbers of germinal center B cells compared to those in wild-type mice, which was a result of enhanced apoptosis. Survival signals in B cells were initiated by engagement of the integrin α 4 β 1 and activation of the downstream kinase Akt. In the absence of CD37, integrin clustering and function were impaired, and activation of the Akt survival pathway was defective. Thus, long-lived plasma cells rely on the tetraspanin CD37 to enable integrin-Akt survival signaling. Signaling by the serine and threonine kinase Akt (also known as protein kinase B), a pathway that is common to all eukaryotic cells, is central to cell survival, proliferation, and gene induction. We sought to elucidate the mechanisms underlying regulation of the kinase activity of Akt in the immune system. We found that the four-transmembrane protein CD37 was essential for B cell survival and long-lived protective immunity. CD37-deficient ( Cd37 −/− ) mice had reduced numbers of immunoglobulin G (IgG)–secreting plasma cells in lymphoid organs compared to those in wild-type mice, which we attributed to increased apoptosis of plasma cells in the germinal centers of the spleen, areas in which B cells proliferate and are selected. CD37 was required for the survival of IgG-secreting plasma cells in response to binding of vascular cell adhesion molecule 1 to the α 4 β 1 integrin. Impaired α 4 β 1 integrin–dependent Akt signaling in Cd37 −/− IgG-secreting plasma cells was the underlying cause responsible for impaired cell survival. CD37 was required for the mobility and clustering of α 4 β 1 integrins in the plasma membrane, thus regulating the membrane distribution of α 4 β 1 integrin necessary for activation of the Akt survival pathway in the immune system.