Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells
Cindy S. Ma, Nathan J. Hare, Kim E. Nichols, Loic Dupré, Grazia Andolfi, Maria-Grazia Roncarolo, Stephen Adelstein, Philip D. Hodgkin, Stuart G. Tangye
Cindy S. Ma, Nathan J. Hare, Kim E. Nichols, Loic Dupré, Grazia Andolfi, Maria-Grazia Roncarolo, Stephen Adelstein, Philip D. Hodgkin, Stuart G. Tangye
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Article Immunology

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

Cindy S. Ma, Nathan J. Hare, Kim E. Nichols, Loic Dupré, Grazia Andolfi, Maria-Grazia Roncarolo, Stephen Adelstein, Philip D. Hodgkin, Stuart G. Tangye

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XLP patients have a severe reduction of memory (CD27+) B cells. (A) PBMC...
XLP patients have a severe reduction of memory (CD27+) B cells. (A) PBMCs from 21 healthy donors, 14 XLP patients, and 18 CVID patients were labeled with anti-CD20 mAb, and the frequency of B cells in the lymphocyte population was determined. The number of B cells per milliliter of blood was then enumerated. (B) PBMCs were labeled with anti-CD20 and anti-CD27 mAbs and the frequency and number of memory (CD27+) B cells/ml of blood were quantitated. The histogram (A) and dot plots (B) are from 1 representative healthy donor, 1 XLP patient, and 1 CVID patient. The graphs show the data points for all donors and patients examined, with the mean frequency and number of cells per milliliter represented by the column graphs and horizontal lines, respectively. Significant differences are indicated. *P < 0.05; ***P < 0.001.