Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells

Abstract

X-linked lymphoproliferative disease (XLP) is an often-fatal immunodeficiency characterized by hypogammaglobulinemia, fulminant infectious mononucleosis, and/or lymphoma. The genetic lesion in XLP, SH2D1A, encodes the adaptor protein SAP (signaling lymphocytic activation molecule-associated [SLAM-associated] protein); however, the mechanism(s) by which mutations in SH2D1A causes hypogammaglobulinemia is unknown. Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells. The few memory cells detected were IgM(+), revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, which indicates that the block in differentiation in vivo is B cell extrinsic. This possibility is supported by the finding that XLP CD4(+) T cells did not efficiently differentiate into IL-10(+) effector cells or provide optimal B cell help in vitro. Importantly, the B cell help provided by SAP-deficient CD4(+) T cells was improved by provision of exogenous IL-10 or ectopic expression of SAP, which resulted in increased IL-10 production by T cells. XLP CD4(+) T cells also failed to efficiently upregulate expression of inducible costimulator (ICOS), a potent inducer of IL-10 production by CD4(+) T cells. Thus, insufficient IL-10 production may contribute to hypogammaglobulinemia in XLP. This finding suggests new strategies for treating this immunodeficiency.

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

“…B cells: PBMCs were incubated with mAbs to CD20, CD27, CD10, IgG and IgA, and the frequency of total memory (CD20 + CD27 + CD10 − ) and switched memory B cells determined 21, 22 .…”

T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell–Cell Contact Mediated through SLAMF6 and SAP

“…Although, the absolute number of total B cells in XLP patients is normal (38), these patients exhibit a marked reduction in their PB memory B cell population (39-41), and Fig. 7 E-F.…”

“…Although the absolute number of total B cells in XLP patients is normal (38), these patients exhibit a marked reduction in their PB memory B cell population (39-41). However, previous analysis of the B cells in XLP patients revealed an increase in the circulating immature/transitional B cells (46).…”

Follicular Helper T Cells in Systemic Lupus Erythematosus: Why Should They Be Considered as Interesting Therapeutic Targets?

“…Indeed, SAP-deficient CD4 + T cells have an impaired capacity to stably interact with cognate B cells, resulting in a failure to induce B cell clonal expansion [32]. Moreover, patients with X-linked Lymphoproliferative disease (XLP), an immunodeficiency resulting from mutations in the SH2D1A gene which encodes SAP, harbor humoral defects characterized by hypogammaglobulinemia and reduced numbers of T FH [33]. B cells thus play a key role in the T FH maturation step by both acting as APC and stabilizing T FH -GC B cell interactions through ICOSL and SLAM.…”