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Journal of Virology, March 2007, p. 2349-2358, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01910-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Tissue-Specific Regulation of CD8+ T-Lymphocyte Immunodominance in Respiratory Syncytial Virus Infection{triangledown}

Sujin Lee,1,3 Scott A. Miller,4 David W. Wright,1,4 Michael T. Rock,1 and James E. Crowe Jr.1,2,3*

Departments of Pediatrics,1 Microbiology and Immunology,2 The Program for Vaccine Sciences, Vanderbilt University Medical Center,3 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 372324

Received 6 September 2006/ Accepted 5 December 2006

Cytotoxic T lymphocytes (CTLs) are critical for control of respiratory syncytial virus (RSV) infection in humans and mice. To investigate cellular immune responses to infection, it is important to identify major histocompatibility complex (MHC) class I-restricted CTL epitopes. In this study, we identified a new RSV-specific, H-2Kd-restricted subdominant epitope in the M2 protein, M2127-135 (amino acids 127 to 135). This finding allowed us to study the frequency of T lymphocytes responding to two H-2Kd-presented epitopes in the same protein following RSV infection by enzyme-linked immunospot (ELISPOT) and intracellular cytokine assays for both lymphoid and nonlymphoid tissues. For the subdominant epitope, we identified an optimal nine-amino-acid peptide, VYNTVISYI, which contained an H-2Kd consensus sequence with Y at position 2 and I at position 9. In addition, an MHC class I stabilization assay using TAP-2-deficient RMA-S cells transfected with Kd or Ld indicated that the epitope was presented by Kd. The ratios of T lymphocytes during the peak CTL response to RSV infection that were specific for M282-90 (dominant) to T lymphocytes specific for M2127-135 (subdominant) were approximately 3:1 in the spleen and 10:1 in the lung. These ratios were observed consistently in primary or secondary infection by the ELISPOT assay and in secondary infection by MHC/peptide tetramer staining. The number of antigen-specific T lymphocytes dropped in the 6 weeks after infection; however, the proportions of T lymphocytes specific for the immunodominant and subdominant epitopes were maintained to a remarkable degree in a tissue-specific manner. These studies will facilitate investigation of the regulation of immunodominance of RSV-specific CTL epitopes.

* Corresponding author. Mailing address: T-2220 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2905. Phone: (615) 343-8064. Fax: (615) 343-4456. E-mail: james.crowe{at}vanderbilt.edu.

{triangledown} Published ahead of print on 20 December 2006.

Journal of Virology, March 2007, p. 2349-2358, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01910-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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