T1D: CD8+ T Cell Subsets Associated with Clinical Response to Alefacept

Scientists from the Benaroya Research Institute and the Immune Tolerance Network in Seattle, Washington have shown that memory CD8+ T cells with an “exhausted-like” phenotype are associated with an indicator of clinical outcome among type 1 diabetics treated with the CD2 inhibitor Alefacept.

Using data from the T1DAL study, a phase 2 clinical trial that evaluated the efficacy of Alefacept for treating type 1 diabetes, the team discovered that two distinct populations of CD8+ T cells are correlated with the enhanced preservation of endogenous insulin production among patients suffering from the disease.

Their work, published in the Journal of Clinical Insight under the title, “Exhausted-like CD8 T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects,” has implications for the current understanding of T lymphocyte biology in the context of this devastating autoimmune disorder.

“Our motivation was to elucidate immunologic mechanisms governing response to biologic therapy in Type 1 Diabetes (T1D), an autoimmune disease for which there is no approved therapy,” senior author Dr. Peter Linsley explained to ImmunoFrontiers.

“Our previous studies had shown linkage between levels of exhausted CD8 T cells and therapeutic benefit after treatment of T1D subjects with the anti-T cell monoclonal antibody, teplizumab. Our hypothesis for the current study was that T cell exhaustion was also linked to treatment with alefacept, another anti-T cell therapy.”

The researchers discovered the T cell populations using RNA sequencing and other techniques. “Our studies integrated RNA-sequencing (RNA-seq), flow- and mass- cytometry (CyTOF) methods with blood samples from a clinical trial with alefacept,” Dr. Linsley continued.

“Using these methods we identified two CD8 T cell subsets linked to clinical response; one that was maintained, and another that recovered post-treatment in subjects showing treatment benefit.”

“These populations were distinct from one another, and shared characteristics of the exhausted CD8 cells previously seen in responders to teplizumab. However, these subsets differed in showing reciprocal expression of CD8 T and NK cell markers (GZMB, CD57 and inhibitory KIR genes), versus T cell activation and differentiation markers (PD1 and CD28).”

“The most important contribution of our study was to demonstrate a previously unknown linkage between CD8 T cell exhaustion and NK-like CD8 T cells.”

Moving forwards, the scientists plan to investigate the how these T cell populations develop, and whether they are related. “We plan to use single cell analysis to determine lineage relationships between exhausted CD8 T cells and NK-like CD8 T cells,” Dr. Linsley stated.

Dr. Linsley’s take-home message for readers: “T cell exhaustion can be linked to therapeutic benefit in T1D. We believe that elucidating the linkage between T cell exhaustion and therapeutic benefit may lead to better biomarkers and treatments in T1D and, perhaps, other autoimmune diseases.”

The authors were Kirsten E Diggins, Elisavet Serti, Virginia S Muir, Mario G Rosasco, TingTing Lu, Elisa Balmas, Gerald T Nepom, S Alice Long, and Peter S Linsley.

Read about the latest research in the field of immunology from ImmunoFrontiers.

Diggins KE, Serti E, Muir VS, et al. (2020) Exhausted-like CD8 T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects. JCI Insight 142680.