CD98hc facilitates B cell proliferation and adaptive humoral immunity

Abstract

Proliferation of antigen-specific lymphocytes and resulting clonal expansion is essential for adaptive immunity. We report that B cell-specific deletion of CD98hc reduced antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc didn’t impair early B cell activation, but did inhibit later activation of the MAP kinase Erk1/2 and down regulation of the p27 cell cycle inhibitor. Reconstitution of CD98hc-deficient B cells with CD98hc mutants revealed that the integrin-binding domain of CD98hc is required, but the amino acid transport function of CD98hc is dispensable, for B cell proliferation. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored appearance of CD98hc in vertebrates.

CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

“…Indeed, in light of our results, CD98hc appears to be not a mere marker for epidermal proliferative keratinocytes (Lemaître et al, 2005) but a crucial actor in skin homeostasis endowed with defined intrinsic functions. Our data, which are in agreement with previous studies showing dependence on CD98hc for proliferation of nonepithelial cells (Cantor et al, 2009;Fogelstrand et al, 2009), further widen the notion that CD98hc expression provides cells with a profound selective advantage.…”

CD98 at the crossroads of adaptive immunity and cancer

“…Overexpression or crosslinking of CD98hc stimulates FAK and AKT phosphorylation Rintoul et al, 2002) (Fenczik et al, 1997), and deletion of CD98hc impairs integrin signaling (Feral et al, 2005). This integrin signaling function of CD98hc is dependent on the transmembrane and cytoplasmic domains (Fenczik et al, 2001), the same region that is crucial for lymphocyte proliferation (Cantor et al, 2009;Cantor et al, 2011) and for cellular transformation caused by overexpression of CD98hc (Henderson et al, 2004). CD98hc can thus regulate integrin signaling, and integrins are crucial for tumor progression through mechanotransduction and control of anchorage-independent growth.…”

“…To address this issue, our group genetically deleted CD98hc in B cells using CD19-Cre (Cantor et al, 2009). Similar to the results in T cells, CD98hc is not required for B cell compartmentalization or their initial activation, but is crucial for B cell clonal expansion (Cantor et al, 2009). CD98-null B cells display strikingly reduced proliferation after stimulation with strong mitogens, and thus are unable to differentiate into plasma cells.…”

“…Indeed, through this nutrient function, CD98 can contribute to the survival and growth of many cell types (Cho et al, 2004;Reynolds et al, 2007). Importantly, surface expression of the light chain is dependent on the presence of the heavy chain, whereas the isolated heavy chain can be expressed without light chains (Cantor et al, 2009;Cantor et al, 2011;Mastroberardino et al, 1998;Teixeira et al, 1987). Thus, CD98hc functions in amplifying integrin signaling and in the transport of amino acids; both of these functions can contribute to cell survival and proliferation.…”

“…Both B and T cell clonal expansion rely on the capacity of lymphocytes to accelerate from a resting state to sustained rapid proliferation. Several molecules and mechanisms assist in this process, including growth cytokines or receptors (Nelson and Willerford, 1998;Weaver et al, 2007), adhesion molecules (Mitchell and Williams, 2010), anti-apoptotic proteins (Hildeman et al, 2007) and the vertebrate-specific transmembrane protein CD98 (Cantor et al, 2009;Cantor et al, 2011).…”