Thus, TCRβ diversity is important for optimal TCRαβ pairing and function when TCRα is limiting. Immune T cells play a key role in limiting viral, bacterial, and parasitic infections. Both the CD8+ and the CD4+ cells use specific TCR to recognize epitopes composed of peptide (p) bound to MHC glycoproteins expressed on the surface of infected cells. Following TCR-mediated activation, T cells proliferate, and produce anti-viral cytokines (e.g. IFN-γ and TNF) and cytotoxic effector molecules that function to destroy the pMHC-marked cells. Epitope-specific TCR are selected from pools of naïve precursors that consists of ∼107 (in mice) and ∼108 (in humans) distinct

TCRαβ heterodimers 1, 2 assembled from variable (Vα and Vβ)

and constant (Cα and Cβ) regions. As expected, immune T cells are often characterized by reproducible pMHC-specific biases in TCR Vβ usage 3 and, less frequently, by a limited spectrum of TCR Vα selection 4, 5. The extent Quizartinib in vitro of TCR diversity in an immune repertoire has been related to CTL-mediated control and pathogen escape in CD8+ T-cell BAY 73-4506 responses to viruses 6, 7. Most of the diversity in TCR/pMHCI interactions rests in the hypervariable complementarity-determining regions (CDR1, CDR2, and CDR3) involved in TCR-pMHCI binding 8. CDR3β provides the predominant contact in at least some of the antigenic peptides bound inside the groove of the MHC molecule 9, 10. However, the CDR1α, CDR2α, and CDR3α loops also contribute greatly to TCR repertoire diversity and mediate important interactions with antigenic peptides and/or MHC determinants 5, 11, 12. The CDR3β and CDR3α regions reflect the clonal characteristics of immune TCR repertoires. In general, TCR repertoires can be either broad, consisting of numerous clonotypes of different CDR3 aa sequences, CDR3 length, and J regions, or restricted

to a few clonotypes that show similar Jβ and CDR3 characteristics. 4��8C TCR repertoires can be also defined as “public” (same clonotypes found in all individuals) or completely “private” (unique to the individual) 3. The exact mechanisms underlying generation of public and private TCR repertoires are far from clear. Influenza virus infection of C57BL/6 (B6, H2b) mice elicits immunodominant CD8+ T-cell responses to peptides from the viral influenza nucleoprotein (NP) and influenza acid polymerase (PA) complexed with the H2Db (DbNP366 and DbPA224), and subdominant CD8+ sets, including those toward the basic polymerase (PB) peptide presented by H2Kb (KbPB1703). Analysis of TCR-CDR3β sequence variability and clone prevalence showed predominantly private and diverse TCRβ sequences for DbPACD8+ T cells 13, but a limited, and substantially public, TCRβ repertoire for the DbNPCD8+ set 14, 15. Thus, influenza infection of B6 mice provides a readily accessible experimental system for dissecting the nexus between TCR repertoire diversity and antiviral efficacy for immune CD8+ T cells.