The yin/yang balance of the MHC-self-immunopeptidome (original) (raw)
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Nature Immunology, 2014
The strength of self-peptide-major histocompatibility complex (MHC) recognition dictates naïve CD8 + T cell homeostasis, but its effect on foreign antigen reactivity is controversial. As CD5 expression correlates with self-recognition, we studied CD5 lo and CD5 hi naïve CD8 + T cells. Gene expression characteristics suggested CD5 hi cells were better poised for reactivity and differentiation compared to the CD5 lo population, and we found that the CD5 hi pool exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during recognition of foreign antigen. Yet foreign peptide-MHC recognition was similar for both subsets. Thus, CD8 + T cells with higher self-reactivity dominate the immune response against foreign antigens, with implications for T cell repertoire diversity and autoimmunity. The nature of the TCR interaction with foreign peptide-MHC (pMHC) complexes dictates the response magnitude and differentiation characteristics of antigen specific T cells 1-4. In addition studies suggest TCR interactions with self-pMHC also impact the naïve T cell response to foreign-pMHC 5-11. Thymic positive selection and naïve T cell homeostasis require low affinity TCR recognition of self-pMHC ligands 12-16 , but there is controversy about how such interactions affect the subsequent response to foreign-pMHC: published studies argue self-pMHC recognition enhances 6 or diminishes 7 the response to foreign antigens, or selectively impairs sensitivity to low-affinity foreign ligands 14. However, those reports investigated the impact of self-pMHC withdrawal rather than studying how the degree of self-pMHC sensitivity influences the T cell response to foreign-pMHC. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Immunity, 2002
Branch the periphery at much higher levels than in the thymus. National Cancer Institute In addition, mature T cells express 5-to 10-fold more 2 Veterinary Resources Program surface TCR than their DP thymocyte precursors (Robey National Institutes of Health and Fowlkes, 1994). As a consequence, interactions be-Bethesda, Maryland 20892 tween TCR and self-MHC/peptide complexes that were 3 Transplantation Unit of low avidity in the thymus may translate into signifi-Massachusetts General Hospital cantly higher avidity interactions in the periphery. Boston, Massachusetts 02114 Two different mechanisms have been offered as po-4 Division of Therapeutic Proteins and tential explanations for why autoimmunity usually does 5 Laboratory of Pediatric and Respiratory not occur. One proposal, which we will refer to as "tun-Viral Diseases ing," posits that the activation threshold of mature T Food and Drug Administration cells is not fixed but is dynamically regulated by encoun-Bethesda, Maryland 20892 ters with self-MHC/peptide complexes in the periphery
Nature Communications, 2014
The role of the T-cell receptor (TCR) in commitment of thymocytes to regulatory CD4 þ Foxp3 þ and conventional CD4 þ Foxp3 À T-cell lineages remains controversial. According to the prevailing view, commitment to the former lineage, in contrast to the latter, requires that high affinity TCRs bind rare class II MHC/peptide complexes presented in 'thymic niches', which could explain differences between their TCR repertoires. Here we challenge this view and show that the binding of identical TCRs to the same ubiquitously expressed MHC/ peptide complex often directs thymocytes to both CD4 þ lineages, indicating that the TCR affinity does not play the instructive role, and that restricted presentation of peptides in 'thymic niches' is not necessary for selection of CD4 þ Foxp3 þ T cells. However, depending on whether immature thymocytes bound the ligand predominantly with low or high affinity, the repertoires of regulatory and conventional CD4 þ T cells were correspondingly similar or mostly different, suggesting that negative rather than positive selection sets them apart.
Adaptation of TCR Repertoires to Self-Peptides in Regulatory and Nonregulatory CD4+ T Cells
The Journal of Immunology, 2007
Currently, it is not understood how the specificity of the TCR guides CD4 ؉ T cells into the conventional lineage (Tconv) vs directing them to become regulatory (Treg) cells defined by the Foxp3 transcription factor. To address this question, we made use of the "Limited" (LTD) mouse, which has a restricted TCR repertoire with a fixed TCR chain and a TCR␣ chain minilocus. The TCR repertoires of Tconv and Treg cells were equally broad, were distinct, yet overlapped significantly, representing a less strict partition than previously seen between CD4 and CD8 T cells. As a group, the CDR3␣ motifs showed a significant trend to higher positive charge in Treg than in Tconv cells. The Tconv and Treg repertoires were both reshaped between thymus and periphery. Reducing the array of peptides presented by MHC class II molecules by introducing the H2-DM o/o mutation into the LTD mouse led to parallel shifts in the repertoires of Tconv and Treg cells. In both cases, the CDR3␣ elements were entirely different and strikingly shortened, relative to normal LTD mice. These peculiar sequences conferred reactivity to wild-type MHC class II complexes and were excluded from the normal repertoire, even among Treg cells, indicating that some forms of self-reactivity are incompatible with selection into the Treg lineage. In conclusion, the Treg repertoire is broad, with distinct composition and characteristics, yet significantly overlapping and sharing structural constraints with the repertoire of conventional CD4 ؉ T cells.
A role for “self” in T-cell activation
Seminars in Immunology, 2007
The mechanisms by which ␣ T-cells are selected in the thymus and then recognize peptide MHC (pMHC) complexes in the periphery remain an enigma. Recent work particularly with respect to quantification of T-cell sensitivity and the role of self-ligands in T-cell activation has provided some important clues to the details of how TCR signaling might be initiated. Here, we highlight recent experimental data that provides insights into the initiation of T-cell activation and also discuss the main controversies and uncertainties in this area.
Proceedings of the National Academy of Sciences, 2004
To study competition between naïve and memory T cells, we examined proliferation of adoptively transferred naïve CD8 + T cells in lymphopenic recipients or recipients containing a clonal population of CD8 + T cells. We find a hierarchy in the extent of T cell proliferation that appears to correlate with the strength of T cell receptor (TCR)-self-peptide-MHC (pepMHC) interactions. CD8 + T cells also proliferate in recipients containing a full complement of CD8 + cells with a different TCR if the transferred T cells experience stronger TCR-self-pepMHC interactions than the resident T cells. Furthermore, CD8 + T cells proliferate in recipients that contain memory CD8 + cells with a different TCR, but in this case the relative strengths of TCR-self-pepMHC interactions are not as critical. In contrast, CD8 + T cells do not proliferate significantly in recipients harboring naïve or memory CD8 + cells that bear the same TCR as the transferred cells. These results suggest that, among naïve ...