title: Physiological mechanisms of regulating alloimmunity: cytokines, CTLA-4, CD25+ cells, and the alloreactive T cell clone size.
abstract: The mechanisms underlying physiological regulation of alloimmune responses remain poorly defined. We investigated the roles of cytokines, CTLA-4, CD25(+) T cells, and apoptosis in regulating alloimmune responses in vivo. Two murine cardiac transplant models were used, B10.D2 (minor mismatch) and C57BL/6 (major mismatch), into BALB/c recipients. Recipients were wild type, STAT4(-/-) (Th1 deficient), or STAT6(-/-) (Th2 deficient) mice. Minor mismatched allografts were accepted spontaneously in approximately 70% of wild type and STAT4(-/-) mice. By contrast, there was significantly shorter graft survival in minor mismatched STAT6(-/-) mice. Either the adoptive transfer of STAT4(-/-) splenocytes or the administration of IL-4Fc fusion protein into STAT6(-/-) mice resulted in long term graft survival. Blocking CTLA-4 signaling accelerated the rejection in all recipients, but was more pronounced in the minor combination. This was accompanied by an increased frequency of alloreactive T cells. Furthermore, CTLA-4 blockade regulated CD4(+) or CD8(+) as well as Th1 or Th2 alloreactive T cells. Finally, while anti-CD25 treatment prolonged graft survival in the major mismatched combination, the same treatment accelerated graft rejection in the minor mismatched group. The latter was associated with an increased frequency of alloreactive T cells and inhibition of T cell apoptosis. These data demonstrate that cytokine regulation, CTLA-4 negative signaling, and T cell apoptosis play critical roles in regulating alloimmunity, especially under conditions where the alloreactive T cell clone size is relatively small.
authors.affiliation: Department of Medicine, Children's Hospital, Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Akira
authors.initials: A
authors.lastname: Yamada
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Sigrid E
authors.initials: SE
authors.lastname: Sandner
authors.forename: Alberto
authors.initials: A
authors.lastname: Sanchez-Fueyo
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D060908:CTLA-4 Antigen; D048429:Cell Size / Q000276:immunology / Q000502:physiology; D002999:Clone Cells; D016207:Cytokines / Q000502:physiology*; D006085:Graft Survival / Q000502:physiology; D016027:Heart Transplantation / Q000502:physiology; D006650:Histocompatibility Testing; D018796:Immunoconjugates; D007519:Isoantigens / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D018655:Lymphocyte Count; D008285:Major Histocompatibility Complex / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007519:Isoantigens; D015778:Minor Histocompatibility Antigens; D015375:Receptors, Interleukin-2; D000069594:Abatacept