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Ilhem Messaoudi, Joël LeMaoult, Jose A. Guevara-Patino, Beatrix M. Metzner, and Janko Nikolich-ugich

Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006

Address correspondence to Janko Nikolich-ugich, Vaccine and Gene Therapy Institute, Oregon Health & Science University, West Campus, 505 NW 185th Ave., Beaverton, OR 97006. Phone: (503) 418-2752; Fax: (503) 418-2764; email: nikolich{at}ohsu.edu

Peripheral T cell diversity is virtually constant in the young, but is invariably reduced in aged mice and humans. CD8⁺ T cell clonal expansions (TCE) are the most drastic manifestation of, and possible contributors to, this reduced diversity. We show that the presence of TCE results in reduced CD8⁺, but not CD4⁺, T cell diversity, and in functional inability to mobilize parts of the CD8⁺ T cell repertoire affected by TCE. In the model of herpes simplex virus (HSV)-1 infection of B6 mice, >90% of the responding CD8⁺ T cells use Vß10 or Vß8 and are directed against a single glycoprotein B (gB_498-505) epitope, gB-8p. We found that old animals bearing CD8⁺ TCE within Vß10 or Vß8 families failed to mount an effective immune response against HSV-1, as judged by reduced numbers of peptide-major histocompatibility complex tetramer⁺ CD8 T cells and an absence of antiviral lytic function. Furthermore, Vß8 TCE experimentally introduced into young mice resulted in lower resistance to viral challenge, whereas Vß5⁺ TCE induced in a similar fashion did not impact viral resistance. These results demonstrate that age-related TCE functionally impair the efficacy of antiviral CD8⁺ T cell immunity in an antigen-specific manner, strongly suggesting that TCE are not the mere manifestation of, but are also a contributing factor to, the immunodeficiency of senescence.

Key Words: aging • TCR • T cell clonal expansions • repertoire diversity • antiviral immunity

J.A. Guevara-Patino's present address is Dept. of Surgery, Pritzker Medical School, University of Chicago, 924 E. 57th Ave., Chicago, IL 60637.

B.M. Metzner's present address is Medigene, Inc., Lochhamer Str. 11, 85152 Martinsried, Germany.

Abbreviations used in this paper: ATX, adult thymectomy; CTLp, TEL precursors; FCM, flow cytofluorometry; pMHC, peptide-MHC; TCE, T cell clonal expansion(s).

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