Exhausted-like CD8+ T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects.
JCI Insight
; 6(3)2021 02 08.
Article
in En
| MEDLINE
| ID: mdl-33351781
ABSTRACT
Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic ß 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
C-Peptide
/
CD8-Positive T-Lymphocytes
/
Diabetes Mellitus, Type 1
/
Alefacept
Type of study:
Clinical_trials
Limits:
Adolescent
/
Adult
/
Child
/
Female
/
Humans
/
Male
Language:
En
Journal:
JCI Insight
Year:
2021
Document type:
Article
Affiliation country:
United States