title: Increasing T-cell age reduces effector activity but preserves proliferative capacity in a murine allogeneic major histocompatibility complex-mismatched bone marrow transplant model.
abstract: Aging of T cells is characterized by a series of alterations in surface antigen expression and a concomitant decline in functional activity in many assays. We have extended this analysis by comparing the ability of T cells from mice of different ages to cause graft-versus-host disease (GVHD) by using a parent into F(1) model (C57BL/6 T cells into C57BL/6 x C3H host animals). Young (3-5 months), adult (12-14 months), or old (19-24 months) T cells were introduced into irradiated F(1) hosts. Animals that had undergone transplantation were assessed for clinical and pathologic evidence of GVHD and for survival. At a given T-cell dose (2 x 10(6) cells), there was a T-cell (donor) age-dependent decline in severity of GVHD, with all recipients of young T cells succumbing to lethal GVHD, 75% of recipients of adult T cells succumbing, and no deaths occurring among recipients of old T cells. In vivo CD4 T-cell expansion was greater for young than old T-cell groups after transplantation, whereas old CD8 cells showed enhanced in vivo expansion compared with young cells. Among CD4 and CD8 cells, the T-cell receptor repertoire, surface antigen expression on activated cells, and homing receptor function were similar for all ages after expansion in vivo. The progeny of old T cells reisolated after transplantation expressed type 1 cytokines (interferon-gamma and tumor necrosis factor-alpha) at a lower frequency than young cells and had decreased cytolytic function against H-2(k)-bearing target cells. This provides a partial explanation for the decreased GVHD. Carboxyfluorescein diacetate succinimidyl ester labeling of transplanted cells showed comparable rates of proliferation when comparing GVHD-competent (12 months) and GVHD-incompetent (19 months) T cells in both syngeneic and F(1) host animals. We suggest that the lack of effector activity demonstrated by old T cells in vivo is a reflection of a cell-autonomous defect downstream of signals required for antigen-driven proliferation.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. friedman@scripps.edu
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Friedman
authors.forename: Onder
authors.initials: O
authors.lastname: Alpdogan
authors.forename: Marcel R m
authors.initials: MR
authors.lastname: van den Brink
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Daniel
authors.initials: D
authors.lastname: Hurwitz
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Boyd
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burakoff
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002455:Cell Division / Q000276:immunology*; D016922:Cellular Senescence / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D014184:Transplantation, Homologous / Q000276:immunology*