CD8+ T cell self-tolerance permits responsiveness but limits tissue damage

Truckenbrod, Emily Nestor; Burrack, Kristina S.; Knutson, Todd P.; Silva, Henrique Borges da; Block, Katharine E.; O’Flanagan, Stephen; Stagliano, Katie R; Hurwitz, Arthur A.; Fulton, Ross B.; Renkema, Kristin R.; Jameson, Stephen C.

doi:10.7554/elife.65615

Cited by 9 publications

(7 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study shows interesting parallels to a recent report by Truckenbrod et al [41] who analyzed polyclonal CD8 T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking Trp2. Similar to our data, Trp2-tet + T cells in Trp2 + mice showed a naïve phenotype.…”

Section: Discussionsupporting

confidence: 86%

MHC I tetramer staining tends to overestimate the number of functionally relevant self‐reactive CD8 T cells in the preimmune repertoire

2023

View full text Add to dashboard Cite

Previous studies that used peptide‐MHC (pMHC) tetramers (tet) to identify self‐specific T cells have questioned the effectiveness of thymic‐negative selection. Here, we used pMHCI tet to enumerate CD8 T cells specific for the immunodominant gp33 epitope of lymphocytic choriomeningitis virus glycoprotein (GP) in mice transgenically engineered to express high levels of GP as a self‐antigen in the thymus. In GP‐transgenic mice (GP+), monoclonal P14 TCR+ CD8 T cells that express a GP‐specific TCR could not be detected by gp33/Db‐tet staining, indicative of their complete intrathymic deletion. By contrast, in the same GP+ mice, substantial numbers of polyclonal CD8 T cells identifiable by gp33/Db‐tet were present. The gp33‐tet staining profiles of polyclonal T cells from GP+ and GP‐negative (GP−) mice were overlapping, but mean fluorescence intensities were ∼15% lower in cells from GP+ mice. Remarkably, the gp33‐tet+ T cells in GP+ mice failed to clonally expand after lymphocytic choriomeningitis virus infection, whereas those of GP− mice did so. In Nur77GFP‐reporter mice, dose‐dependent responses to gp33 peptide‐induced TCR stimulation revealed that gp33‐tet+ T cells with high ligand sensitivity are lacking in GP+ mice. Hence, pMHCI tet staining identifies self‐specific CD8 T cells but tends to overestimate the number of truly self‐reactive cells.

show abstract

Section: Discussionsupporting

confidence: 86%

MHC I tetramer staining tends to overestimate the number of functionally relevant self‐reactive CD8 T cells in the preimmune repertoire

2023

View full text Add to dashboard Cite

show abstract

“…Our data suggest that a relatively strong tone of TCR signaling in CD4SP thymocytes continues to be relatively strong after these cells localize to peripheral lymphoid organs. Nur77-GFP HI cells, particularly Population D cells, may arise from incomplete negative selection of self-reactive T cells in the thymus [26][27][28][29][30]. We propose that chronic strong tonic TCR signaling promotes negative feedback that can lead to hyporesponsiveness or tolerance to counterbalance their increased reactivity to self-pMHC [31].…”

Section: Discussionmentioning

confidence: 98%

Strong basal/tonic TCR signals are associated with negative regulation of naive CD4⁺ T cells

Zinzow-Kramer

Eggert

Scharer

et al. 2022

Preprint

View full text Add to dashboard Cite

Tonic TCR signaling occurs constitutively in response to self-peptides presented by MHC (pMHC). Tonic TCR signal intensity correlates with Nur77-GFP reporter transgene expression. A broad range of Nur77-GFP is first detectable in post-selection thymocytes and persists in mature T cells. Nur77-GFPHI Ly6C− CD4+ T cells experience the strongest tonic TCR signaling and exhibit functional hypo-responsiveness to foreign pMHC stimulation. Gene expression analyses suggest similarities between the programs induced by strong tonic TCR signaling and T cell activation. However, the strongest tonic TCR signals also appear to induce expression of negative regulators, including coinhibitory receptors. Analysis of chromatin accessibility similarly suggest that strong tonic TCR signaling correlates with differentially higher accessibility of over 3000 chromatin regions in or near genes that encode positive and negative regulators of T cell activation. We propose that very strong tonic TCR signaling induces mechanisms of negative feedback to recalibrate T cell sensitivity.

show abstract

“…This is consistent with early studies showing rapid Nur77 expression during negative selection of thymocytes (Cheng et al, 1997). Recent studies have also provided evidence for mature CD8 + T cells that recognize self-pMHC but exhibit reduced functionality or tolerance (Truckenbrod et al, 2021). Such tolerogenic responses are evident in T cells that experience constitutive agonist TCR stimulation in mice unperturbed by infection or inflammatory mediators (Trefzer et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Eggert

Zinzow-Kramer

et al. 2023

Preprint

View full text Add to dashboard Cite

The cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8+ T cells to subsequent agonist TCR stimulation remains incompletely understood. We investigated how naive CD8+ T cells that experienced relatively low or high levels of TCR signaling in response to self-antigens respond to stimulation with foreign antigens. A transcriptional reporter of Nr4a1 (Nur77-GFP) revealed substantial heterogeneity of the amount of TCR signaling naive CD8+ T cells accumulate in the steady state. Nur77-GFPHIcells exhibited diminished T cell activation and secretion of IFN γ and IL-2 relative to Nur77-GFPLOcells in response to agonist TCR stimulation. Differential gene expression analyses revealed upregulation of genes associated with acutely stimulated T cells in Nur77-GFPHIcells but also increased expression of negative regulators such as the phosphatase Sts1. Responsiveness of Nur77-GFPHIcells to TCR stimulation was partially restored at the level of IFN γ secretion by deficiency of Sts1 or the ubiquitin ligase Cbl-b. Our data suggest that extensive accumulation of TCR signaling during steady state conditions induces a recalibration of the responsiveness of naive CD8+ T cells through gene expression changes and negative regulation, at least in part, dependent on Sts1 and Cbl-b. This cell-intrinsic negative feedback loop may allow the immune system to limit the autoreactive potential of highly self-reactive naive CD8+ T cells.

show abstract

CD8+ T cell self-tolerance permits responsiveness but limits tissue damage

Cited by 9 publications

References 69 publications

MHC I tetramer staining tends to overestimate the number of functionally relevant self‐reactive CD8 T cells in the preimmune repertoire

MHC I tetramer staining tends to overestimate the number of functionally relevant self‐reactive CD8 T cells in the preimmune repertoire

Strong basal/tonic TCR signals are associated with negative regulation of naive CD4⁺ T cells

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Contact Info

Product

Resources

About

CD8+ T cell self-tolerance permits responsiveness but limits tissue damage

Cited by 9 publications

References 69 publications

MHC I tetramer staining tends to overestimate the number of functionally relevant self‐reactive CD8 T cells in the preimmune repertoire

MHC I tetramer staining tends to overestimate the number of functionally relevant self‐reactive CD8 T cells in the preimmune repertoire

Strong basal/tonic TCR signals are associated with negative regulation of naive CD4+ T cells

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

Contact Info

Product

Resources

About

Strong basal/tonic TCR signals are associated with negative regulation of naive CD4⁺ T cells