CD8؉ T-cell responses control lymphocytic choriomeningitis virus (LCMV) infection in H-2 b mice. Although antigen-specific responses against LCMV infection are well studied, we found that a significant fraction of the CD8 ؉ CD44 hi T-cell response to LCMV in H-2 b mice was not accounted for by known epitopes. We screened peptides predicted to bind major histocompatibility complex class I and overlapping 15-mer peptides spanning the complete LCMV proteome for gamma interferon (IFN-␥) induction from CD8 ؉ T cells derived from LCMV-infected H-2 b mice. We identified 19 novel epitopes. Together with the 9 previously known, these epitopes account for the total CD8 ؉ CD44 hi response. Thus, bystander T-cell activation does not contribute appreciably to the CD8 ؉ CD44 hi pool. Strikingly, 15 of the 19 new epitopes were derived from the viral L polymerase, which, until now, was not recognized as a target of the cellular response induced by LCMV infection. The L epitopes induced significant levels of in vivo cytotoxicity and conferred protection against LCMV challenge. Interestingly, protection from viral challenge was best correlated with the cytolytic potential of CD8 ؉ T cells, whereas IFN-␥ production and peptide avidity appear to play a lesser role. Taken together, these findings illustrate that the LCMV-specific CD8 ؉ T-cell response is more complex than previously appreciated. A central feature of CD8ϩ T-cell responses is immunodominance, a phenomenon by which only a subset of the potentially immunogenic peptides in an antigen are in fact recognized following natural infection or deliberate immunization (33). Experimental infection of laboratory mice with lymphocytic choriomeningitis virus (LCMV) is a widely utilized system for studying the mechanisms of immunodominance in viral infection (3,24,29,31). Viral clearance in the course of acute LCMV infection in the mouse is critically dependent upon the CD8 ϩ cytotoxic T lymphocyte (CTL) response. Following acute infection of C57BL/6J (H-2 b ) mice with the Armstrong strain of LCMV, a large proportion of the viral CD8 ϩ T-cell response is directed against two epitopes derived from the glycoprotein (GP) (amino acids 33 to 41) and the nucleoprotein (NP) (amino acids 396 to 404), as well as several other epitopes, including 31). Recent data demonstrate that, following acute LCMV infection, 85 to 95% of CD8 ϩ T cells are CD44 hi and that the known LCMV epitopes plus the newly defined GP70-77, NP166-175, and NP235-243 account for only about 80% of this CD8 ϩ CD44 hi T-cell pool (17). Thus, based on these studies (which were restricted to the NP and GP gene products), some questions remain on the possible contribution of non-LCMV-specific T cells recruited by bystander activation to the CD8 ϩ CD44 hi T-cell pool.The products of the L-RNA segment, L (RNA polymerase) and Z (Zinc binding protein), have been discounted as a potential source of CTL epitopes because of the reported low expression of L (10, 12) and the small size of Z. Indeed, previous studies searching for novel...
CD8+ T cell responses control lymphocytic choriomeningitis virus (LCMV) infection in H-2b mice. Although antigen-specific responses against LCMV infection are well studied, we found that up to one third of the CD8+CD44hi response to LCMV in H-2b mice was not accounted for by known epitopes. We screened peptides predicted to bind MHC Class I, and overlapping 15-mer peptides spanning the complete LCMV proteome for their capacity to induce interferon-γ (IFNγ) production from CD8+ T cells derived from LCMV-infected H-2b mice. We identified thirteen novel epitopes. These together with the 7 previously known epitopes account for the total CD8+CD44hi response, diminishing the possible role for bystander T cell activation. Strikingly, 9 out of the 13 new epitopes were derived from the viral L polymerase, which, until now, was not recognized as a target of the cellular response induced by LCMV infection. The L epitopes induced significant levels of in vivo cytotoxicity and conferred protection against LCMV challenge. Interestingly, protection from viral challenge was best correlated with the cytolytic potential of CD8+ T cells, whereas IFNγ production and peptide avidity appear to play a lesser role. Taken together, these findings illustrate that the LCMV-specific CD8+T cell response is more complex than previously appreciated.
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