Clonal regulatory T cells specific for a red blood cell autoantigen in human autoimmune hemolytic anemia.
Regulatory T (Tr) cells have the potential to treat immune-mediated disease, but cloning such cells for study from patients with autoimmune disease has proven difficult. Here, we describe autoantigen-specific, interleukin-10 (IL-10)-secreting Tr cell clones recovered ex vivo from a patient with autoimmune hemolytic anemia (AIHA) and characterize their phenotype, origin, and regulatory function. These IL-10+ Tr cells recognized a peptide, 72H-86L, derived from the Rh red blood cell autoantigen and shared phenotypic characteristics with both natural and inducible Tr cells. The clones also expressed different Tr markers depending on activation state: high levels of CD25 and LAG-3 when expanding nonspecifically, but FoxP3 after activation by the autoantigen they recognize. Despite a discrete Tr phenotype, these cells stably expressed the T helper 1 (Th1) signature transcription factor T-bet, suggesting they derive from Th1 T cells. Finally, the contribution of CTLA-4 in activating these IL-10+ Tr cells was confirmed by analyzing responses to transgenic B7.1-like molecules that preferentially bind either CD28 or CTLA-4. Overall, these Tr cells have a functional phenotype different from those described in previous studies of human Tr populations, which have not taken account of antigen specificity, and understanding their properties will enable them to be exploited therapeutically in AIHA.
Ward
Frank J
FJ
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, UK. mmd475@abdn.ac.uk
Hall
Andrew M
AM
Cairns
Lindsay S
LS
Leggat
Arabella S
AS
Urbaniak
Stanislaw J
SJ
Vickers
Mark A
MA
Barker
Robert N
RN
D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D060908:CTLA-4 Antigen; D002460:Cell Line; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D017710:Lymphocyte Transfusion; D010455:Peptides / Q000276:immunology*; D012204:Rh-Hr Blood-Group System / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D000093322:Lymphocyte Activation Gene 3 Protein; D000098815:T-bet Transcription Factor
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides; D012204:Rh-Hr Blood-Group System; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016753:Interleukin-10; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human