Re-establishing peripheral tolerance in the absence of CTLA-4: complementation by wild-type T cells points to an indirect role for CTLA-4.
CTLA-4 plays an important role in the down-regulation of activated T cells and in the establishment of peripheral tolerance. It has been hypothesized that CTLA-4 on the cell surface signals directly into T cells during primary immune responses, resulting in intrinsic T cell down-regulation. It is not known, however, whether CTLA-4 directly inhibits the less intense activating signals received by autoreactive T cells in the periphery. We investigated whether CTLA-4 acts intrinsically upon self-reactive cells in vivo, or whether it inhibits autoreactive cells indirectly, in a non-cell autonomous manner. The adoptive transfer of CTLA-4-deficient splenocytes or Thy 1(+) cells into recombinase-activating gene 2-deficient mice resulted in fatal inflammation and tissue destruction similar to that seen in CTLA-4-deficient mice. When an equivalent number of splenocytes or Thy 1(+) cells from wild-type animals was transferred with the CTLA-4-deficient cells, recipient mice survived indefinitely. Since CTLA-4 was absent in the T cells responsible for the inflammatory phenotype, the down-regulation of these autoreactive cells must have been facilitated indirectly by wild-type Thy 1(+) cells. In addition, a rapid reduction in the ratio of CTLA-4-deficient to wild-type cells was observed. We propose two possible indirect mechanisms by which CTLA-4 may function in the establishment and maintenance of peripheral tolerance.
Tivol
Elizabeth A
EA
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee WI 53201, USA.
Gorski
Jack
J
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015329:Gene Rearrangement, T-Lymphocyte; D005816:Genetic Complementation Test; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D017634:Self Tolerance; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018800:Thy-1 Antigens / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D018796:Immunoconjugates; C499308:Rag2 protein, mouse; D018800:Thy-1 Antigens; C064655:V(D)J recombination activating protein 2; D000069594:Abatacept