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Departments of
* Medical Microbiology and Immunology and
Surgery, Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada
CD4 T cells frequently help to activate CD8 T and B cells that effect transplant rejection. However, CD4 T cells alone can reject transplants, either directly or indirectly. The relative effectiveness of indirect CD4 immunity in rejecting different types of allogeneic grafts is unknown. To address this, we used a TCR transgenic mouse model in which indirect CD4 alloimmunity alone can be studied. We challenged transgenic recipients with hematopoietic cells and shortly thereafter skin transplants that could only be rejected indirectly, and observed Ag-specific indirect donor B cell and skin rejection, but not T cell elimination, reflecting a state of split tolerance. Deficiency of indirect CD4 alloimmunity in donor T cell rejection was also apparent when acute indirect rejection of donor islets occurred despite generation and maintenance of mixed T cell chimerism, due to migration of the few passenger T cells into recipient circulation. Although passenger lymphocytes delayed indirect islet rejection, they enhanced rejection by a full repertoire capable of both direct and indirect reactivity. Interestingly, the persistence of chimerism was associated with the eventual development of tolerance, as demonstrated by acceptance of donor skin grafts given late to hematopoietic cell recipients, and hyporesponsiveness of transgenic T cells from islet recipients in vitro. Mechanistically, tolerance was recessive and associated with progressive down-regulation of CD4. Collectively, our data indicate that indirect CD4 immunity is not equally destructive toward different types of allogeneic grafts, the deficiency of which generates split tolerance. The futility of these responses can convert immunity into tolerance.
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1 This work was supported by a grant from the Canadian Institutes of Health Research.
2 W.F.N.C. is supported by doctoral research studentships from the Muttart Diabetes Research and Training Centre and the Canadian Diabetes Association.
3 C.C.A. is supported by a scholar award from the Alberta Heritage Foundation for Medical Research.
4 Address correspondence and reprint requests to Dr. Colin C. Anderson, 1074 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada. E-mail address: colinand{at}ualberta.ca
5 Abbreviations used in this paper: KO, knockout; FLC, fetal liver cell; STZ, streptozotocin; DTH, delayed-type hypersensitivity; WT, wild type.
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  P. Dutta, M. Molitor-Dart, J. L. Bobadilla, D. A. Roenneburg, Z. Yan, J. R. Torrealba, and W. J. Burlingham Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice Blood, October 22, 2009; 114(17): 3578 - 3587. [Abstract] [Full Text] [PDF]
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