Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity.
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor on T cells essential for maintaining T cell homeostasis and tolerance to self. Mice lacking CTLA-4 develop an early onset, fatal breakdown in T cell tolerance. Whether this autoimmune disease occurs because of the loss of CTLA-4 function in regulatory T cells, conventional T cells, or both is unclear. We show here that lack of CTLA-4 in regulatory T cells leads to aberrant activation and expansion of conventional T cells. However, CTLA-4 expression in conventional T cells prevents aberrantly activated T cells from infiltrating and fatally damaging nonlymphoid tissues. These results demonstrate that CTLA-4 has a dual function in maintaining T cell tolerance: CTLA-4 in regulatory T cells inhibits inappropriate naïve T cell activation and CTLA-4 in conventional T cells prevents the harmful accumulation of self-reactive pathogenic T cells in vital organs.
Jain
Nitya
N
Department of Pathology, Graduate Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Nguyen
Hai
H
Chambers
Cynthia
C
Kang
Joonsoo
J
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D002454:Cell Differentiation; D002465:Cell Movement; D051858:Forkhead Transcription Factors / Q000276:immunology; D007108:Immune Tolerance; D007113:Immunity, Innate; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse