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Increasing t-cell age reduces effector activity but preserves proliferative capacity in a murine allogeneic major histocompatibility complex - mismatched bone marrow transplant model

Academic Article
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Overview

authors

  • Friedman, Jeffrey
  • Alpdogan, O.
  • van den Brink, M. R. M.
  • Liu, C.
  • Hurwitz, D.
  • Boyd, A.
  • Kupper, T. S.
  • Burakoff, S. Y.

publication date

  • July 2004

journal

  • Biology of Blood and Marrow Transplantation  Journal

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.

subject areas

  • Aging
  • Animals
  • Bone Marrow Transplantation
  • Cell Aging
  • Cell Division
  • Female
  • Graft vs Host Disease
  • Lymphocyte Activation
  • Major Histocompatibility Complex
  • Mice
  • Signal Transduction
  • T-Lymphocytes
  • Transplantation, Homologous
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Research

keywords

  • T-cell expansion
  • aging T cells
  • cytokines
  • effector activity
  • graft-versus-host disease
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Identity

International Standard Serial Number (ISSN)

  • 1083-8791

Digital Object Identifier (DOI)

  • 10.1016/j.bbmt.2004.03.005

PubMed ID

  • 15205666
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Additional Document Info

start page

  • 448

end page

  • 460

volume

  • 10

issue

  • 7

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