Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

Long, S. Alice; Thorpe, Jerill; DeBerg, Hannah A.; Gersuk, Vivian H.; Eddy, James A.; Harris, Kristina M.; Ehlers, Mario R.; Herold, Kevan C.; Nepom, Gerald T.; Linsley, Peter S.

doi:10.1126/sciimmunol.aai7793

Cited by 192 publications

(217 citation statements)

References 59 publications

(103 reference statements)

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“…Similar findings in type I diabetic patients treated with the anti-CD3 monoclonal antibody teplizumab demonstrate the relevance of these new insights into peripheral CD8 tolerance [64]. A population of hypoproliferative EOMES+TIGIT+KLRG1+ CD8+ T cells is readily identified in the blood of patients with the greatest response to anti-CD3 treatment [64]. …”

Section: Ii) Tolerance Mechanisms Associated With Transient Mixed Chimentioning

confidence: 70%

“…Furthermore, downregulated expression of hypoxia-inducible factor HIFα in tolerant CD8+ T cells [62] is aligned with the low metabolic requirement and the high expression of VHL in exhausted T cells [63]. Similar findings in type I diabetic patients treated with the anti-CD3 monoclonal antibody teplizumab demonstrate the relevance of these new insights into peripheral CD8 tolerance [64]. A population of hypoproliferative EOMES+TIGIT+KLRG1+ CD8+ T cells is readily identified in the blood of patients with the greatest response to anti-CD3 treatment [64].…”

Section: Ii) Tolerance Mechanisms Associated With Transient Mixed Chimentioning

confidence: 91%

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Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Zuber

Sykes

2017

Trends in Immunology

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Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field, recently achieved in the clinic by combining bone marrow transplantation with kidney transplantation following non-myeloablative conditioning. At high levels of chimerism, such protocols can permit central deletional tolerance, yet with a significant risk of graft-versus-host disease (GVHD). In contrast, transient chimerism-based tolerance is devoid of GVHD risk and appears to initially depend on regulatory T cells followed by a gradual, presumably peripheral, clonal deletion of donor-reactive T cells. Here, we review recent mechanistic insights into tolerance and the development of more robust and safer protocols for tolerance induction that will be guided by innovative immune monitoring tools.

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Section: Ii) Tolerance Mechanisms Associated With Transient Mixed Chimentioning

confidence: 70%

Section: Ii) Tolerance Mechanisms Associated With Transient Mixed Chimentioning

confidence: 91%

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Zuber

Sykes

2017

Trends in Immunology

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“…Bulk RNA-seq libraries were sequenced to target depths of ~10 million reads. RNA-seq pipeline analysis methods have previously been described (25). Quality metrics for aligned reads were obtained using the Picard (v.1.56) suite of tools (https://broadinstitute.github.io/picard/).…”

Section: Methodsmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4+ T Cells in Peripheral Blood of Subjects with Type 1 Diabetes

Cerosaletti¹,

Barahmand-pour-Whitman²,

Yang³

et al. 2017

The Journal of Immunology

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The significance of islet antigen-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects is unclear, partly because similar cells are also found in healthy control (HC) subjects. We hypothesized that key disease-associated cells would show evidence of prior antigen exposure, inferred from expanded T cell receptor (TCR) clonotypes, and essential phenotypic properties in their transcriptomes. To test this, we developed single-cell RNA sequencing (RNA-seq) procedures for identifying TCR clonotypes and transcript phenotypes in individual T cells. We applied these procedures to analysis of islet- antigen reactive CD4+ memory T cells from the blood of T1D and HC individuals following activation with pooled immunodominant islet peptides. We found extensive TCR clonotype sharing in antigen-activated cells, especially from individual T1D subjects, consistent with in vivo T cell expansion during disease progression. The expanded clonotype from one T1D subject was detected at repeat visits spanning more than 15 months, demonstrating clonotype stability. Notably, we found no clonotype sharing between subjects, indicating a predominance of “private” TCR specificities. Expanded clones from two T1D subjects recognized distinct IGRP peptides, implicating this molecule as a trigger for CD4+ T cell expansion. While overall transcript profiles of cells from HC and T1D subjects were similar, profiles from the most expanded clones were distinctive. Our findings demonstrate that islet- antigen reactive CD4+ memory T cells with unique antigen specificities and phenotypes are expanded during disease progression and can be detected by single-cell analysis of peripheral blood.

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“…The mechanism of action of teplizumab was initially thought to deplete T cells similar to other immunotherapies that target T cells, such as OKT3, thymoglobulin, and Campath (anti-CD52) [6]. More recently, we reported an increase in the frequency of circulating central memory CD8 T cells in clinical responders [7], and further investigation revealed that accumulation of partially exhausted CD8 T cells, characterized by co-expression of TIGIT and KLRG1 together with high levels of EOMES-associated gene networks, was associated with successful response to teplizumab therapy [8]. These studies suggested that teplizumab therapy, rather than acting as a depleting or blocking antibody, may have agonist properties that lead to changes in the composition of differentiation and activation status within the circulating pool of CD3-expressing T cells.…”

Section: Introductionmentioning

confidence: 99%

Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes

Long

Thorpe

Herold

et al. 2017

Cellular Immunology

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The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57−KLRG1−PD-1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57−KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127). The observed phenotypic changes across cell types were associated with favorable response to treatment in the subgroup of study participants that did not develop anti-drug antibodies after the first course of therapy. These findings provide new insights on the duration and complexity of T cell modulation with teplizumab therapy in recent onset T1D, and in addition, suggest that coordinated immune mechanisms of tolerance that favor CD4 Treg function and restrain CD4 non-Treg and CD8 T cell activation may contribute to treatment success.

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Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

Cited by 192 publications

References 59 publications

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4+ T Cells in Peripheral Blood of Subjects with Type 1 Diabetes

Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes

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