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Exhausted-like CD8+ T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects
- Source :
- JCI Insight, Vol 6, Iss 3 (2021)
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical investigation, 2021.
-
Abstract
- Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic β cells through immune perturbation and serve as resources to elucidate immunological mechanisms in health and disease. In the T1DAL trial of alefacept (LFA3-Ig) in recent-onset T1D, endogenous insulin production was preserved in 30% of subjects for 2 years after therapy. Given our previous findings linking exhausted-like CD8+ T cells to beneficial response in T1D trials, we applied unbiased analyses to sorted CD8+ T cells to evaluate their potential role in T1DAL. Using RNA sequencing, we found that greater insulin C-peptide preservation was associated with a module of activation- and exhaustion-associated genes. This signature was dissected into 2 CD8 memory phenotypes through correlation with cytometry data. These cells were hypoproliferative, shared expanded rearranged TCR junctions, and expressed exhaustion-associated markers including TIGIT and KLRG1. The 2 phenotypes could be distinguished by reciprocal expression of CD8+ T and NK cell markers (GZMB, CD57, and inhibitory killer cell immunoglobulin-like receptor [iKIR] genes), versus T cell activation and differentiation markers (PD-1 and CD28). These findings support previous evidence linking exhausted-like CD8+ T cells to successful immune interventions for T1D, while suggesting that multiple inhibitory mechanisms can promote this beneficial cell state.
- Subjects :
- Autoimmunity
Immunology
Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 6
- Issue :
- 3
- Database :
- Directory of Open Access Journals
- Journal :
- JCI Insight
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.37b23ff4286140899c19dfc035864cd1
- Document Type :
- article
- Full Text :
- https://doi.org/10.1172/jci.insight.142680