Conventional and Regulatory CD4+ T Cells That Share Identical TCRs Are Derived from Common Clones

Abstract

Results from studies comparing the diversity and specificity of the TCR repertoires expressed by conventional (Tconv) and regulatory (Treg) CD4+ T cell have varied depending on the experimental system employed. We developed a new model in which T cells express a single fixed TCRα chain, randomly rearranged endogenous TCRβ chains, and a Foxp3-GFP reporter. We purified CD4+Foxp3- and CD4+Foxp3+ cells, then performed biased controlled multiplex PCR and high throughput sequencing of endogenous TCRβ chains. We identified >7,000 different TCRβ sequences in the periphery of 5 individual mice. On average, ~12% of TCR sequences were expressed by both conventional and regulatory populations within individual mice. The CD4+ T cells that expressed shared TCR sequences were present at higher frequencies compared to T cells expressing non-shared TCRs. Furthermore, nearly all (>90%) of the TCR sequences that were shared within mice were identical at the DNA sequence level, indicating that conventional and regulatory T cells that express shared TCRs are derived from common clones. Analysis of TCR repertoire overlap in the thymus reveals that a large proportion of Tconv and Treg sharing observed in the periphery is due to clonal expansion in the thymus. Together these data show that there are a limited number of TCR sequences shared between Tconv and Tregs. Also, Tconv and Tregs sharing identical TCRs are found at relatively high frequencies and are derived from common progenitors, of which a large portion are generated in the thymus.

CD4+T cells mediate protection against Zika associated severe disease in a mouse model of infection

“…Knowing that CD4 + T cells were required for control of ZIKV infection and that we could detect a strong antigen specific CD4 + T cell response in the mice, we hypothesized that the TCR repertoire specific for the different CD4 epitopes would contain a high degree of diversity. Using techniques we have previously established to identify TCRβ sequences diversity of CD4 + T cells [ 65 ], we noted a striking degree of diversity in the TCRβ sequences for an individual ZIKV-specific epitope within a mouse and between mice ( Fig 5 ). We were unable to detect shared “public” TCRs for any epitope between mice confirming our hypothesis that the ZIKV epitope specific T cell responses were clonally diverse suggesting a broadly reactive T cell pool.…”

Cytomegalovirus infection in HIV-infected and uninfected individuals is characterized by circulating regulatory T cells of unconstrained antigenic specificity

“…A recent study showed that 12% of T-cell receptors were shared by Tregs and conventional effector T cells at the DNA level suggesting a common progenitor cell [31]. Tregs also tend to express markers of the effectors that they target.…”

Shared TCR epitope cross-reactivity could permit dyads of Foxp3+ regulatory and IL-2-producing T cell precursors to escape thymic purge

“…Since SPIRAL mandates antigen-specific inhibition of ineffective T cell responses by Tregs (Usharauli and Kamala, 2018;Pohar et al, 2018;Akkaya et al, 2019), their sensing of IL-2 as a proxy for such ineffective T cell responses must be antigen-specific as well (Setoguchi et al, 2005;Almeida et al, 2006;Amado et al, 2013;Liu et al, 2015). In other words, Tregs cannot just sense IL-2 produced by random T cells but instead must share antigen-specificity in the form of crossreactivity with such IL-2 producing T cells (Wolf et al, 2016). Applying this principle to the thymus suggests that IL-2p T cell and Treg precursors whose progeny recognize similar epitopes in the periphery via shared epitope cross-reactivity must be able to do likewise in the thymus as well.…”