title: Prolonged graft survival in older recipient mice is determined by impaired effector T-cell but intact regulatory T-cell responses.
abstract: Elderly organ transplant recipients represent a fast growing segment of patients on the waiting list. We examined age-dependent CD4(+) T-cell functions in a wild-type (WT) and a transgenic mouse transplant model and analyzed the suppressive function of old regulatory T-cells. We found that splenocytes of naïve old B6 mice contained significantly higher frequencies of T-cells with an effector/memory phenotype (CD4(+)CD44(high)CD62L(low)). However, in-vitro proliferation (MLR) and IFNgamma-production (ELISPOT) were markedly reduced with increasing age. Likewise, skin graft rejection was significantly delayed in older recipients and fewer graft infiltrating CD4(+)T-cells were observed. Old CD4(+) T-cells demonstrated a significant impaired responsiveness as indicated by diminished proliferation and activation. In contrast, old alloantigen-specific CD4(+)CD25(+)FoxP3(+) T-cells demonstrated a dose-dependent well-preserved suppressor function. Next, we examined characteristics of 18-month old alloreactive T-cells in a transgenic adoptive transfer model. Adoptively transferred old T-cells proliferated significantly less in response to antigen. Skin graft rejection was significantly delayed in older recipients, and graft infiltrating cells were reduced. In summary, advanced recipient age was associated with delayed acute rejection and impaired CD4(+) T-cell function and proliferation while CD4(+)CD25(+)FoxP3(+) T-cells (Tregs) showed a well-preserved function.
authors.affiliation: Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Denecke
authors.forename: Damanpreet Singh
authors.initials: DS
authors.lastname: Bedi
authors.forename: Xupeng
authors.initials: X
authors.lastname: Ge
authors.forename: Irene Kyung-Eun
authors.initials: IK
authors.lastname: Kim
authors.forename: Anke
authors.initials: A
authors.lastname: Jurisch
authors.forename: Anne
authors.initials: A
authors.lastname: Weiland
authors.forename: Antje
authors.initials: A
authors.lastname: Habicht
authors.forename: Xian C
authors.initials: XC
authors.lastname: Li
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D019264:Adoptive Transfer; D000367:Age Factors; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology* / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D019707:Receptors, Chemokine; D007371:Interferon-gamma