Enhanced engagement of CTLA-4 induces antigen-specific CD4+CD25+Foxp3+ and CD4+CD25- TGF-beta 1+ adaptive regulatory T cells.
CTLA-4 is a critical negative regulator of T cell response and is instrumental in maintaining immunological tolerance. In this article, we report that enhanced selective engagement of CTLA-4 on T cells by Ag-presenting dendritic cells resulted in the induction of Ag-specific CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)TGF-beta1(+) adaptive Tregs. These cells were CD62L(low) and hyporesponsive to stimulation with cognate Ag but demonstrated a superior ability to suppress Ag-specific effector T cell response compared with their CD62L(high) counterparts. Importantly, treatment of mice with autoimmune thyroiditis using mouse thyroglobulin (mTg)-pulsed anti-CTLA-4 agonistic Ab-coated DCs, which results in a dominant engagement of CTLA-4 upon self-Ag presentation, not only suppressed thyroiditis but also prevented reemergence of the disease upon rechallenge with mTg. Further, the disease suppression was associated with significantly reduced mTg-specific T cell and Ab responses. Collectively, our results showed an important role for selective CTLA-4 signaling in the induction of adaptive Tregs and suggested that approaches that allow dominant CTLA-4 engagement concomitant with Ag-specific TCR ligation can be used for targeted therapy.
Li
Ruobing
R
Department of Surgery, University of Illinois, Chicago 60612, USA.
Perez
Nicolas
N
Karumuthil-Melethil
Subha
S
Prabhakar
Bellur S
BS
Holterman
Mark J
MJ
Vasu
Chenthamarakshan
C
D000818:Animals; D018033:Antibodies, Bispecific / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D019041:L-Selectin / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1; D019041:L-Selectin