title: Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells.
abstract: T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8(+) cytotoxic T lymphocyte effector function and differentiation, but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed toward human CMV, expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bet(hi)Eomes(hi/lo)), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) compared with subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-bet(int)Eomes(hi)). Paradoxically, the T-bet(hi)Eomes(hi/lo) dominant populations that efficiently recognized endogenous antigen demonstrated lower intrinsic avidity for pMHC, whereas T-bet(int)Eomes(hi) subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8(+) T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status, and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.
authors.affiliation: Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Corey
authors.initials: C
authors.lastname: Smith
authors.forename: Diah
authors.initials: D
authors.lastname: Elhassen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Wynn
authors.forename: Vijayendra
authors.initials: V
authors.lastname: Dasari
authors.forename: Judy
authors.initials: J
authors.lastname: Tellam
authors.forename: Siok-Keen
authors.initials: SK
authors.lastname: Tey
authors.forename: Sweera
authors.initials: S
authors.lastname: Rehan
authors.forename: Yu Chih
authors.initials: YC
authors.lastname: Liu
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005434:Flow Cytometry; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology; D054353:Perforin / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D000956:Antigens, Viral; D016207:Cytokines; C491199:EOMES protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes