Exhausted CD8+ T cell populations linked to beneficial response in T1D

Next generation sequencing (NGS) have enabled an unprecedented view of the phenotypic properties of T cells responding to biologic therapy. NGS tools have enabled us, in collaboration with the Long Lab, to discover that beneficial response to teplizumab therapy, a biologic agent recently approved by the FDA for treatment of type 1 diabetes (T1D), is linked to CD8+ T cell exhaustion.

More recently, we showed that beneficial response to a second T cell-targeting agent, alefacept, was also linked to T cell exhaustion. In this case, we found two distinct exhausted cell populations, one resembling the exhausted two CD8+ T cells found in teplizumab treated subjects, and a second distinct population of NK-like CD8+ T cells.

To probe relationships between exhausted T cell subsets more deeply, we relied on a technique we developed, in collaboration with the Cerosaletti Lab, a novel single-cell RNA-seq (scRNA-seq) approach for determining both TCR sequences and full transcriptome phenotypes from individual antigen-specific T cells. We have extended these published procedures to analyze shared ancestry and phenotypic heterogeneity of exhausted T cells associated with beneficial therapeutic response. These experiments have revealed previously unknown shared ancestry between exhausted CD8+ T cells and NK-like CD8+ T cells in peripheral blood.

Linsley Lab Res Proj Inline - Exhausted CD8+ T Cell
Linking clonally related viral specific-specific CD8+ T cells to cell clusters correlating with response to alefacept treatment in T1D. Each dot represents an individual CD8+ T cell, plotted by single cell RNA-seq profiles; arcs link cells sharing identical TCR sequences. Provided by E. Witkop, manuscript in preparation.

We are probing molecular mechanisms and causality links between exhausted cell populations and response to therapy.