title: Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions.
abstract: T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity-hence reactivity to self-and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2bhaplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 Ld-restricted epitope, derived from the Rop7 protein of Toxoplasma gondii We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Lee Kim
authors.initials: LK
authors.lastname: Swee
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore.|Department of Biological Sciences, Immunology Programme, National University of Singapore, Singapore.
authors.forename: Zhen Wei
authors.initials: ZW
authors.lastname: Tan
authors.affiliation: Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Sanecka
authors.affiliation: Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Harshil
authors.initials: H
authors.lastname: Patel
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore.|Department of Biological Sciences, Immunology Programme, National University of Singapore, Singapore.
authors.forename: Gijsbert
authors.initials: G
authors.lastname: Grotenbreg
authors.affiliation: Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK eva.frickel@crick.ac.uk.
authors.forename: Eva-Maria
authors.identifier: 0000-0002-9515-3442
authors.initials: EM
authors.lastname: Frickel
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA ploegh@wi.mit.edu.
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002455:Cell Division; D020869:Gene Expression Profiling; D015329:Gene Rearrangement, T-Lymphocyte; D051379:Mice; D015800:Protozoan Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D014123:Toxoplasmosis / Q000235:genetics* / Q000276:immunology
chemical_list: D015800:Protozoan Proteins; D011948:Receptors, Antigen, T-Cell
keywords: CD8 T cells; cell cycle; self-affinity