title: 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.
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia.
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Hare
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.forename: Loic
authors.initials: L
authors.lastname: Dupré
authors.forename: Grazia
authors.initials: G
authors.lastname: Andolfi
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Stephen
authors.initials: S
authors.lastname: Adelstein
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hodgkin
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000917:Antibody Formation; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D017578:Immunoglobulin Class Switching; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D019013:CD40 Antigens; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D016753:Interleukin-10