Aberrant T-cell antigen receptor-mediated responses in autoimmune lymphoproliferative syndrome.
Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of defective lymphocyte apoptosis due to mutations of the Fas receptor and other molecules in the Fas signaling pathway. In addition to accumulation of CD4(-) CD8(-) double-negative (DN) T cells, many patients display a dysregulated cytokine pattern with dysfunctional T cells, suggesting Fas defects may impact pathways of T-cell activation/differentiation. Here, we report two novel mutations in the Fas receptor resulting in an ALPS phenotype. Utilizing flow cytometry, we found anti-CD3 activated CD4(+) T cells from these patients were incapable of fully upregulating activation markers (CD25, CD69, and CD40L) or producing interferon-gamma and IL-2. Additionally, DN T cells were unable to transduce proximal T-cell antigen receptor signals or produce cytokines. Furthermore, DN T cells overexpressed CD57 and phenotypically resembled end-stage effector cells. As DN T cells were essentially anergic, the clinical manifestations of autoimmunity are more likely to be a consequence of aberrant cytokine secretion within the CD4(+) T-cell subpopulation.
Department of Pediatrics, University of Iowa Hospitals and Clinics and Veterans Affairs Medical Center, Iowa City, 52242, USA. Frederick-Goldman@uiowa.edu
Frederick D
FD
Goldman
Rajeev
R
Vibhakar
Jennifer M
JM
Puck
Stephen E
SE
Straus
Zuhair K
ZK
Ballas
Clay
C
Hollenback
Thomas
T
Loew
Anthony
A
Thompson
Kejing
K
Song
Robert T
RT
Cook
D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D002675:Child, Preschool; D003593:Cytoplasm / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013577:Syndrome; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002118:Calcium; D007371:Interferon-gamma; D007376:Interleukin-2; D015847:Interleukin-4; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D019014:fas Receptor; D000099192:CD69 Antigens