Conversations that count: Cellular interactions that drive T cell fate

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Abstract

The relationship between the extrinsic environment and the internal transcriptional network is circular. Naive T cells first engage with antigen‐presenting cells to set transcriptional differentiation networks in motion. In turn, this regulates specific chemokine receptors that direct migration into distinct lymph node niches. Movement into these regions brings newly activated T cells into contact with accessory cells and cytokines that reinforce the differentiation programming to specify T cell function. We and others have observed similarities in the transcriptional networks that specify both CD4+ T follicular helper (T _FH) cells and CD8+ central memory stem‐like (T _SCM) cells. Here, we compare and contrast the current knowledge for these shared differentiation programs, compared to their effector counterparts, CD4+ T‐helper 1 (T _H1) and CD8+ short‐lived effector (T _SLEC) cells. Understanding the interplay between cellular interactions and transcriptional programming is essential to harness T cell differentiation that is fit for purpose; to stimulate potent T cell effector function for the elimination of chronic infection and cancer; or to amplify the formation of humoral immunity and longevity of cellular memory to prevent infectious diseases.

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Most cited references 205

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B cells and tertiary lymphoid structures promote immunotherapy response

Beth A Helmink, Sangeetha M Reddy, Jianjun Gao … (2020)

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

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Defining CD8(+) T cells that provide the proliferative burst after PD-1 therapy.

Se Jin Im, Masao Hashimoto, Michael Gerner … (2016)

Chronic viral infections are characterized by a state of CD8(+) T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8(+) T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8(+) T cells. Here we identify a population of virus-specific CD8(+) T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8(+) T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8(+) T-cell subset was characterized by a unique gene signature that was related to that of CD4(+) T follicular helper (TFH) cells, CD8(+) T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4(+) TH1 cells and CD8(+) terminal effectors. This CD8(+) T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8(+) T cells. These PD-1(+)CD8(+) T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8(+) T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8(+) T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8(+) T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

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Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy

Imran Siddiqui, Karin Schaeuble, Vijaykumar Chennupati … (2019)

Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8+ T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1+PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+PD-1+ and differentiated Tcf1-PD-1+ cells. Ablation of Tcf1+PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+PD-1+ cells were detected among tumor-reactive CD8+ T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.

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Author and article information

Contributors

Joanna R. Groom:

ORCID: https://orcid.org/0000-0001-5251-7835

groom@wehi.edu.au

Journal

Journal ID (nlm-ta): Immunol Rev

Journal ID (iso-abbrev): Immunol Rev

Journal ID (doi): 10.1111/(ISSN)1600-065X

Journal ID (publisher-id): IMR

Title: Immunological Reviews

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0105-2896

ISSN (Electronic): 1600-065X

Publication date (Electronic): 14 February 2021

Publication date (Print): March 2021

Volume: 300

Issue: 1 ( doiID: 10.1111/imr.v300.1 )

Pages: 203-219

Affiliations

[ ¹ ] Division of Immunology Walter and Eliza Hall Institute of Medical Research Parkville Vic. Australia

[ ² ] Department of Medical Biology University of Melbourne Parkville Vic. Australia

Author notes

[*] [* ] Correspondence

Joanna R Groom, Division of Immunology, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Vic. 3052, Australia.

Email: groom@ 123456wehi.edu.au

Author information

Brigette C. Duckworth https://orcid.org/0000-0002-2134-3542

Joanna R. Groom https://orcid.org/0000-0001-5251-7835

Article

Publisher ID: IMR12945

DOI: 10.1111/imr.12945

PMC ID: 8048805

PubMed ID: 33586207

SO-VID: 90ea4075-beac-4abc-ba81-3310adc610a0

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date revision received : 16 December 2020

Date received : 14 November 2020

Date accepted : 24 December 2020

Page count

Figures: 2, Tables: 0, Pages: 17, Words: 16415

Funding

Funded by: National Health and Medical Research Council , open-funder-registry 10.13039/501100000925;

Award ID: GNT1137989

Award ID: GNT1182649

Funded by: Australian Research Council , open-funder-registry 10.13039/501100000923;

Award ID: 130100708

Funded by: Walter and Eliza Hall Centenary Fellowship

Custom metadata

source-schema-version-number 2.0

cover-date March 2021

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:15.04.2021

Keywords: cellular interactions,lymphoid niche,migration,stem‐like memory,t cell differentiation,t follicular helper,transcriptional regulation

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Keywords: cellular interactions, lymphoid niche, migration, stem‐like memory, t cell differentiation, t follicular helper, transcriptional regulation

Conversations that count: Cellular interactions that drive T cell fate

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Gamma Delta T cells

Most cited references 205

B cells and tertiary lymphoid structures promote immunotherapy response

Defining CD8(+) T cells that provide the proliferative burst after PD-1 therapy.

Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy

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