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Understanding How T Cell Receptor Recognition and Signaling Impacts CD8+ T Cell Functional Programming /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Understanding How T Cell Receptor Recognition and Signaling Impacts CD8+ T Cell Functional Programming // Erik Guillen.
Author:	Guillen, Erik,
Description:	1 electronic resource (224 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-09, Section: B.
Contained By:	Dissertations Abstracts International86-09B.
Subject:	Immunology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31843256
ISBN:	9798310144897

Understanding How T Cell Receptor Recognition and Signaling Impacts CD8+ T Cell Functional Programming /
Guillen, Erik,

Understanding How T Cell Receptor Recognition and Signaling Impacts CD8+ T Cell Functional Programming /Erik Guillen. - 1 electronic resource (224 pages)

Source: Dissertations Abstracts International, Volume: 86-09, Section: B.

CD8+ T cells play a critical role in adaptive immunity and are unique in their ability to identify and eliminate pathogen-infected and tumor cells. Effective T cell priming requires T cell receptor (TCR) recognition of cognate antigen, costimulatory, and inflammatory cytokine signals leading to T cell proliferative clonal expansion and the development of potent effector functions. Following an immune response, most primary expanded T cells contract and die while a small fraction transition into long-lived memory CD8+ T (TM) cells. Numerous studies have explored the mechanisms governing the functional characteristics and longevity of CD8+ TM cells. The programming of CD8+ T cells is influenced by cell-extrinsic signals (i.e. priming signals), master transcription factors, and epigenetic modifications. While stronger cognate antigen signals drive greater primary effector responses and larger memory pools, many studies suggest that changes to TCR stimulation do not significantly affect memory CD8+ T cell functions.In this study, we utilize transgenic TCR mouse models, spectral flow cytometry, transcriptomic and epigenetic profiling, and adoptive T cell transfer assays to investigate the role of TCR signals in programming CD8+ TM cells. We hypothesize that the quality of TCR signaling during CD8+ T cell priming is a pivotal factor in shaping TM cell functional features. First, we assessed how TCR signal strength affects naive CD8+ T cells' reliance on cytokines for developing functional memory. Our results indicate that decreasing TCR signaling can impact the formation of functional CD8+ TM cells when IL-2 cytokine signaling becomes limiting. Specifically, CD8+ T cells primed with weaker TCR signals require robust IL-2 signaling to develop fully functional memory, while strong TCR signals are sufficient even if IL-2 signals are lacking. Moreover, CD8+ TM cells generated upon strong TCR and IL-2 priming signals exhibit epigenetic landscapes characterized by a much broader chromatin accessibility than either signal alone, which is associated with enhanced CD8+ TM cell functional fitness. Second, we explored how altering TCR-peptide/MHC interactions during priming affects CD8+ TM cell differentiation. We introduced mutations to known model T cell epitopes that either directly (TCR contact residues) or indirectly (MHC anchor residues) affect TCR interactions with its cognate epitope. We used these mutant epitopes to prime naive antigen-specific CD8+ T cells and examined how it influences T cell fate decisions, memory phenotype, and functional characteristics. Our findings reveal that mutations that indirectly alter how the TCR interacts with its cognate epitope, but not the strength of TCR signaling, can change the fates of CD8+ TM cells, and promote the development of greater central/stem TM cell (TCM/TSCM) like features. These cells expressed increased expression of markers linked to TCM/TSCM cells (e.g., CD62L, EOMES, BCL2), have enhanced chromatin accessibility in stem-cell-related gene promoters (e.g., Lef1, Bcl6, Wnt10). Furthermore, they exhibit superior functional characteristics that include greater clonal re-expansion, more diverse progeny, and improved pathogen clearance.In a separate study, we examined host immunity in Adult T cell Leukemia/Lymphoma (ATLL), an extremely aggressive T cell leukemia driven by the HTLV-1 oncogenic virus. We hypothesized that malignant ATLL cells establish systemic immunosuppression that facilitates quick leukemia progression, and that therapeutic interventions that enhance anti-ATLL CD8+ T cell responses should promote durable remission. Our analysis reveals that ATLL cells display an immunosuppressive phenotype, marked by high expression of markers of regulatory T cells (e.g., FOXP3, HELIOS, CD25, CCR4). Furthermore, we identified a unique subset of phenotypically-exhausted CD8+ T cells in ATLL patients that is expanded during clinical remission and could contribute to effective anti-tumor immunity.Collectively, this thesis work provides insights into CD8+ T cell functions that could inform vaccine designs and adoptive cell therapies against intracellular pathogens and tumors. Our results support the idea that TCR signaling is a major driver of CD8+ T cell differentiation, regulates T cell fate decisions, and dictates TM cell functional programming. Our findings also challenge the assumption that the strongest epitopes are inherently the most effective in inducing long-lasting TM cells, potentially reshaping our thinking of epitope selection for prime/boost strategies in vaccine design and adoptive T cell therapies.

English

ISBN: 9798310144897Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Immunotherapy

Understanding How T Cell Receptor Recognition and Signaling Impacts CD8+ T Cell Functional Programming /
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520 $a CD8+ T cells play a critical role in adaptive immunity and are unique in their ability to identify and eliminate pathogen-infected and tumor cells. Effective T cell priming requires T cell receptor (TCR) recognition of cognate antigen, costimulatory, and inflammatory cytokine signals leading to T cell proliferative clonal expansion and the development of potent effector functions. Following an immune response, most primary expanded T cells contract and die while a small fraction transition into long-lived memory CD8+ T (TM) cells. Numerous studies have explored the mechanisms governing the functional characteristics and longevity of CD8+ TM cells. The programming of CD8+ T cells is influenced by cell-extrinsic signals (i.e. priming signals), master transcription factors, and epigenetic modifications. While stronger cognate antigen signals drive greater primary effector responses and larger memory pools, many studies suggest that changes to TCR stimulation do not significantly affect memory CD8+ T cell functions.In this study, we utilize transgenic TCR mouse models, spectral flow cytometry, transcriptomic and epigenetic profiling, and adoptive T cell transfer assays to investigate the role of TCR signals in programming CD8+ TM cells. We hypothesize that the quality of TCR signaling during CD8+ T cell priming is a pivotal factor in shaping TM cell functional features. First, we assessed how TCR signal strength affects naive CD8+ T cells' reliance on cytokines for developing functional memory. Our results indicate that decreasing TCR signaling can impact the formation of functional CD8+ TM cells when IL-2 cytokine signaling becomes limiting. Specifically, CD8+ T cells primed with weaker TCR signals require robust IL-2 signaling to develop fully functional memory, while strong TCR signals are sufficient even if IL-2 signals are lacking. Moreover, CD8+ TM cells generated upon strong TCR and IL-2 priming signals exhibit epigenetic landscapes characterized by a much broader chromatin accessibility than either signal alone, which is associated with enhanced CD8+ TM cell functional fitness. Second, we explored how altering TCR-peptide/MHC interactions during priming affects CD8+ TM cell differentiation. We introduced mutations to known model T cell epitopes that either directly (TCR contact residues) or indirectly (MHC anchor residues) affect TCR interactions with its cognate epitope. We used these mutant epitopes to prime naive antigen-specific CD8+ T cells and examined how it influences T cell fate decisions, memory phenotype, and functional characteristics. Our findings reveal that mutations that indirectly alter how the TCR interacts with its cognate epitope, but not the strength of TCR signaling, can change the fates of CD8+ TM cells, and promote the development of greater central/stem TM cell (TCM/TSCM) like features. These cells expressed increased expression of markers linked to TCM/TSCM cells (e.g., CD62L, EOMES, BCL2), have enhanced chromatin accessibility in stem-cell-related gene promoters (e.g., Lef1, Bcl6, Wnt10). Furthermore, they exhibit superior functional characteristics that include greater clonal re-expansion, more diverse progeny, and improved pathogen clearance.In a separate study, we examined host immunity in Adult T cell Leukemia/Lymphoma (ATLL), an extremely aggressive T cell leukemia driven by the HTLV-1 oncogenic virus. We hypothesized that malignant ATLL cells establish systemic immunosuppression that facilitates quick leukemia progression, and that therapeutic interventions that enhance anti-ATLL CD8+ T cell responses should promote durable remission. Our analysis reveals that ATLL cells display an immunosuppressive phenotype, marked by high expression of markers of regulatory T cells (e.g., FOXP3, HELIOS, CD25, CCR4). Furthermore, we identified a unique subset of phenotypically-exhausted CD8+ T cells in ATLL patients that is expanded during clinical remission and could contribute to effective anti-tumor immunity.Collectively, this thesis work provides insights into CD8+ T cell functions that could inform vaccine designs and adoptive cell therapies against intracellular pathogens and tumors. Our results support the idea that TCR signaling is a major driver of CD8+ T cell differentiation, regulates T cell fate decisions, and dictates TM cell functional programming. Our findings also challenge the assumption that the strongest epitopes are inherently the most effective in inducing long-lasting TM cells, potentially reshaping our thinking of epitope selection for prime/boost strategies in vaccine design and adoptive T cell therapies.
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650 4 $a Oncology. $3 751006
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653 $a Immunotherapy
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653 $a Tumor cells
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