Biology subjects

Robey, E. A.

Publications and source records attributed to Robey, E. A..

4 recordsLinked to original sources

bioRxiv2020

Novel Vβ specific germline contacts shape an elite controller T cell response

Certain CD8 T cell responses are particularly effective at controlling infection, as exemplified by elite control of HIV in individuals harboring HLA-B57. To understand the structural features that contribute to CD8 T cell elite control, we focused on a strongly protective CD8 T cell response directed against a parasite-derived peptide (HF10) presented by an atypical MHC-I molecule, H-2Ld. This response exhibits a focused TCR repertoire dominated by V{beta}2, and a representative TCR (TG6) in complex with Ld-HF10 reveals an unusual structure in which both MHC and TCR contribute extensively to peptide specificity, along with a parallel footprint of TCR on its pMHC ligand. The parallel footprint is a common feature of V{beta}2-containing TCRs and correlates with an unusual V-V{beta} interface, CDR loop conformations, and V{beta}2-specific germline contacts with peptide. V{beta}2 and Ld may represent "specialist" components for antigen recognition that allow for particularly strong and focused T cell responses.

immunology↗

bioRxiv2020

An unusual MHC molecule generates protective CD8+ T cell responses to chronic infection

The CD8+ T cell response to the intracellular parasite Toxoplasma gondii varies dramatically between mouse strains, resulting in differences in control of the parasite. Protection in BALB/c mice can be attributed to an unusually strong and protective MHC-1 Ld-restricted CD8+ T cell response directed against a peptide derived from the parasite antigen GRA6. The MHC-1 Ld molecule has limited peptide binding compared to conventional MHC molecules such as Kb or Db, which correlates with polymorphisms associated with "elite control" of HIV in humans. To investigate the link between the unusual MHC-1 molecule Ld and the generation of "elite controller" CD8+ T cell responses, we compared the GRA6-Ld specific T cell response to the well-studied OVA-Kb specific response, and demonstrated that GRA6-Ld specific T cells are significantly more protective and resistant to exhaustion in chronic T. gondii infection. To further investigate the connection between limited peptide presentation and robust T cell responses, we used CRISPR/Cas9 to generate mice with a point mutation (W97R) in the peptide-binding groove of Ld that results in broader peptide binding. We investigated the effect of this Ld W97R mutation on another robust Ld-restricted response against the IE1 peptide during Murine Cytomegalovirus (MCMV) infection. This mutation leads to an increase in exhaustion markers in the IE1-Ld specific CD8+ T cell response. Our results indicate that limited peptide binding by MHC-1 Ld correlates with the development of robust and protective CD8+ T cell responses that may avoid exhaustion during chronic infection.

immunology↗

bioRxiv2019

Factors that influence the thymic selection of CD8αα intraepithelial lymphocytes

Thymocytes bearing {beta} T cell receptors (TCR{beta}) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8-expressing intraepithelial lymphocytes (CD8 IELs). The factors that influence the choice between negative selection versus CD8 IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8IEL development, we show that the affinity threshold for CD8 IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

immunology↗

bioRxiv2019

A role for phagocytosis in inducing cell death during thymocyte negative selection

Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, we demonstrate that phagocytosis promotes negative selection, and that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a two-step model for negative selection in which thymocytes initiate the death process following strong TCR signaling, but ultimately depend upon phagocytosis for their timely death. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.

immunology↗