CD8 T Cell Sensory Adaptation Dependent on TCR Avidity for Self-Antigens (original) (raw)

TCR Signal Strength and T Cell Development

Annual Review of Cell and Developmental Biology, 2016

Thymocyte selection involves the positive and negative selection of the repertoire of T cell receptors (TCRs) such that the organism does not suffer autoimmunity, yet has the benefit of the ability to recognize any invading pathogen. The signal transduced through the TCR is translated into a number of different signaling cascades that result in transcription factor activity in the nucleus and changes to the cytoskeleton and motility. Negative selection involves inducing apoptosis in thymocytes that express strongly self-reactive TCRs, whereas positive selection must induce survival and differentiation programs in cells that are more weakly self-reactive. The TCR recognition event is analog by nature, but the outcome of signaling is not. A large number of molecules regulate the strength of the TCR-derived signal at various points in the cascades. This review discusses the various factors that can regulate the strength of the TCR signal during thymocyte development.

Divergent Changes in the Sensitivity of Maturing T Cells to Structurally Related Ligands Underlies Formation of a Useful T Cell Repertoire

Immunity, 1999

Three major alternative hypotheses have been pro- † Lymphocyte Biology Section posed as explanations, the "cosignal/unique peptide," Laboratory of Immunology "quantitative threshold or avidity," and "quality of signal" National Institute of Allergy and Infectious Diseases models. The first postulates that thymocytes simultane-National Institutes of Health ously signaled through the TCR and by the CD28 costim-Bethesda, Maryland 20892 ulatory pathway undergo apoptosis. Epithelial thymic stromal cells mediating positive selection differ from the hematopoietic cells typically involved in negative Summary selection in lacking expression of the CD80/CD86 costimulatory molecules (Punt et al., 1994; Amsen and CD4 ؉ CD8 ؉ thymocyte differentiation requires TCR sig-Kruisbeek, 1996; Kishimoto et al., 1996; Lesage et al., naling induced by self-peptide/MHC ligands. Never-1997). Only thymocytes with TCR recognizing peptide/ theless, the resulting mature T cells are not activated MHC complexes uniquely expressed on the costimulaby these self-complexes, whereas foreign ligands can tory-deficient stromal cells (Nakagawa et al., 1998) are be potent stimuli. Here, we show that the signaling presumed to survive the selection process, preventing properties of TCR change during thymocyte maturaexport

Adaptation by naïve CD4+ T cells to self-antigen–dependent TCR signaling induces functional heterogeneity and tolerance

Proceedings of the National Academy of Sciences, 2019

Naïve CD4+ T cells experience weak T cell receptor (TCR) signals induced by self-peptides presented by MHC II. To investigate how these “basal” TCR signals influence responses to agonist TCR ligand stimulation, we analyzed naïve CD4+ cells expressing varying amounts of CD5, Ly6C, and Nur77-GFP, markers that reflect the strength of basal TCR signaling. Phenotypic analyses indicate that the broadest range of basal TCR signal strength can be visualized by a combination of Nur77-GFP and Ly6C. A range of basal TCR signaling is detectable even in populations that express identical TCRs. Whereas moderate basal TCR signal strength correlates with higher IL-2 secretion at early time points following TCR stimulation, weak basal TCR signaling correlated with higher IL-2 secretion at later time points. We identify a population of Nur77-GFPHI Ly6C− cells that could not be reliably marked by either of CD5, Ly6C, or Nur77-GFP alone. These cells experience the strongest basal TCR signaling, consist...

Contribution of TCR signaling strength to CD8+ T cell peripheral tolerance mechanisms

Journal of immunology (Baltimore, Md. : 1950), 2014

Peripheral tolerance mechanisms are in place to prevent T cells from mediating aberrant immune responses directed against self and environmental Ags. Mechanisms involved in the induction of peripheral tolerance include T cell-intrinsic pathways, such as anergy or deletion, or exogenous tolerance mediated by regulatory T cells. We have previously shown that the density of peptide-MHC class I recognized by the TCR determines whether CD8(+) T cells undergo anergy or deletion. Specifically, using a TCR-transgenic CD8(+) T cell model, we demonstrated that persistent peripheral exposure to low- or high-dose peptides in the absence of inflammatory signals resulted in clonal deletion or anergy of the T cell, respectively. In this study, by altering the affinity of the peptide-MHC tolerogen for TCR, we have confirmed that this mechanism is dependent on the level of TCR signaling that the CD8(+) T cell receives. Using altered peptide ligands (APLs) displaying high TCR affinities, we show that...

Peripheral Tolerance of CD8 T Lymphocytes

Immunity, 2005

Furthermore, a recent report dem-1 Department of Immunology onstrated that TEC-mediated central tolerance could The Scripps Research Institute occur via recognition of antigen displayed by the TECs La Jolla, California 92037 themselves or after transfer of the antigens to BMderived, antigen-presenting cells (APCs) (Gallegos and Bevan, 2004).