Background: How does a limited pool of <108 T cell receptors (TCRs) provide immunity to >1015 antigens?Results: A single TCR can respond to >one million different decamer peptides.Conclusion: This unprecedented level of receptor promiscuity explains how the naïve TCR repertoire achieves effective immunity.Significance: TCR degeneracy has enormous potential to be the root cause of autoimmune disease.

Key Points• MHCI-restricted TCRs exhibit an explicit preference for a single MHCI-peptide length.• Effective CD8 ϩ T-cell immunity can only be achieved by length-matched Ag-specific T-cell clonotypes.␣␤-TCRs expressed at the CD8 ؉ T-cell surface interact with short peptide fragments (p) bound to MHC class I molecules (pMHCI). The TCR/pMHCI interaction is pivotal in all aspects of CD8 ؉ T-cell immunity. However, the rules that govern the outcome of TCR/pMHCI engagement are not entirely understood, and this is a major barrier to understanding the requirements for both effective immunity and vaccination. In the present study, we discovered an unexpected feature of the TCR/pMHCI interaction by showing that any given TCR exhibits an explicit preference for a single MHCI-peptide length. Agonists of nonpreferred length were extremely rare, suboptimal, and often entirely distinct in sequence. Structural analysis indicated that alterations in peptide length have a major impact on antigenic complexity, to which individual TCRs are unable to adapt. This novel finding demonstrates that the outcome of TCR/pMHCI engagement is determined by peptide length in addition to the sequence identity of the MHCI-bound peptide. Accordingly, the effective recognition of pMHCI Ag, which is a prerequisite for successful CD8 ؉ T-cell immunity and protective vaccination, can only be achieved by length-matched Ag-specific CD8 ؉ T-cell clonotypes. (Blood. 2013;121(7):1112-1123)

Killer-cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also impact adaptive T cell-mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple, independent cohorts of HIV-1, hepatitis C virus (HCV) and human T cell leukemia virus (HTLV-1)-infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections.

There is an urgent need for a better understanding of adaptive immunity to Burkholderia pseudomallei, the causative agent of melioidosis that is frequently associated with sepsis or death in patients in Southeast Asia and Northern Australia. The imperative to identify vaccine targets is driven both by the public health agenda in these regions and biological threat concerns. In several intracellular bacterial pathogens, alkyl hydroperoxidase reductases are upregulated as part of the response to host oxidative stress, and they can stimulate strong adaptive immunity. We show that alkyl hydroperoxidase reductase (AhpC) of B. pseudomallei is strongly immunogenic for T cells of ‘humanized’ HLA transgenic mice and seropositive human donors. Some T cell epitopes, such as p6, are able to bind diverse HLA class II heterodimers and stimulate strong T cell immunity in mice and humans. Importantly, patients with acute melioidosis who survive infection show stronger T cell responses to AhpC relative to those who do not. Although the sequence of AhpC is virtually invariant among global B. pseudomallei clinical isolates, a Cambodian isolate varies only in C-terminal truncation of the p6 T cell epitope, raising the possibility of selection by host immunity. This variant peptide is virtually unable to stimulate T cell immunity. For an infection in which there has been debate about centrality of T cell immunity in defense, these observations support a role for T cell immunity to AhpC in disease protection.

Background: Current peptide vaccines may select suboptimal antigen-specific T-cells from polyclonal populations.Results: A combinatorial peptide library screen was used to generate an optimal ligand that could preferentially activate a known effective T-cell clonotype.Conclusion: Rationally designed altered peptide ligands may enable the preferential selection of high quality, antigen-sensitive T-cell clonotypes.Significance: This proof-of-principle study could facilitate the development of more effective peptide vaccination strategies.