Alteration in CD45RBhi/CD45RBlo T-cell ratio following CD45RB monoclonal-antibody therapy occurs by selective deletion of CD45RBhi effector cells.
Tolerance induction by CD45RB monoclonal antibody (mAb) in murine allograft models is associated with an alteration in the CD45RBlo/CD45RBhi T-cell ratio in favor of CD45RBlo T cells, which can function as regulatory cells and promote tolerance. It has been proposed that inversion of the CD45RBhi/CD45RBlo normal T-cell ratio by mAb can occur by down-regulation of CD45RB surface molecules expressed by T cells. Because CD45RB mAb infusion can lead to a reduction in peripheral T cells, we tested whether other mechanisms might participate in the inversion of the CD45RBhi/CD45RBlo ratio, including apoptosis of CD45RBhi cells. We report that CD45RB mAb led to rapid elimination of both CD4+ and CD8+ T cells in vitro. Importantly, CD45RB mAb selectively eliminated CD45RBhi T cells without affecting the viability of CD45RBlo T cells. Furthermore, the death of T cells occurred with a reduction in mitochondrial transmembrane potential and DNA fragmentation but with little evidence of nuclear condensation and cell shrinkage typically found with cells undergoing apoptosis. We propose that CD45RB mAb therapy may promote a dominant regulatory T-cell population that has the capacity to inhibit rejection by the selective elimination of CD45RBhi effector T cells. This occurs by a process that does not involve the classic morphologic features of apoptosis. Strategies that facilitate an inversion of the CD45RBhi/CD45RBlo T-cell subset ratio may improve the efficacy of CD45RB mAb, and therapeutic measures that prevent deletion of CD45RBhi T cells may need to be avoided to achieve tolerance clinically.
Luke
Patrick P W
PP
Department of Surgery, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada. patrick.luke@lhsc.on.ca.
Deng
Jian P
JP
O'Brien
Catherine A
CA
Everest
Michelle
M
Hall
Anne V
AV
Chakrabarti
Subrata
S
O'Connell
Peta J
PJ
Zhong
Robert
R
Jevnikar
Anthony M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001692:Biological Transport / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D005260:Female; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D017493:Leukocyte Common Antigens / Q000032:analysis*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000737:chemistry* / Q000166:cytology* / Q000276:immunology; D014181:Transplantation Immunology
D000911:Antibodies, Monoclonal; D017493:Leukocyte Common Antigens