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Analysis of the TCR Variable Gene Repertoire in Chimpanzees: Identification of Functional Homologs to Human Pseudogenes¹

Dirk Meyer-Olson^*, Kristen W. Brady^*, Jason T. Blackard, Todd M. Allen^*, Sabina Islam^*, Naglaa H. Shoukry, Kelly Hartman^*, Christopher M. Walker and Spyros A. Kalams^2,*,

^* Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129; Gastrointestinal Unit 3, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; Division of Molecular Medicine, Children’s Research Institute, Columbus, OH 43205; and Infectious Diseases Unit, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232

Chimpanzees are used for a variety of disease models such as hepatitis C virus (HCV) infection, where Ag-specific T cells are thought to be critical for resolution of infection. The variable segments of the TCR genes are polymorphic and contain putative binding sites for MHC class I and II molecules. In this study, we performed a comprehensive analysis of genes that comprise the TCR variable gene (TCRBV) repertoire of the common chimpanzee Pan troglodytes. We identified 42 P. troglodytes TCRBV sequences representative of 25 known human TCRBV families. BV5, BV6, and BV7 are multigene TCRBV families in humans and homologs of most family members were found in the chimpanzee TCRBV repertoire. Some of the chimpanzee TCRBV sequences were identical with their human counterparts at the amino acid level. Notably four successfully rearranged TCRBV sequences in the chimpanzees corresponded to human pseudogenes. One of these TCR sequences was used by a cell line directed against a viral CTL epitope in an HCV-infected animal indicating the functionality of this V region in the context of immune defense against pathogens. These data indicate that some TCRBV genes maintained in the chimpanzee have been lost in humans within a brief evolutionary time frame despite remarkable conservation of the chimpanzee and human TCRBV repertoires. Our results predict that the diversity of TCR clonotypes responding to pathogens like HCV will be very similar in both species and will facilitate a molecular dissection of the immune response in chimpanzee models of human diseases.

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