MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4⁺T cells

Abstract

<jats:p>T cell maturation and activation depend upon T cell receptor (TCR) interactions with a wide variety of antigenic peptides displayed in a given major histocompatibility complex (MHC) context. Complementarity-determining region 3 (CDR3) is the most variable part of the TCRα and -β chains, which govern interactions with peptide–MHC complexes. However, it remains unclear how the CDR3 landscape is shaped by individual MHC context during thymic selection of naïve T cells. We established two mouse strains carrying distinct allelic variants of<jats:italic>H2-A</jats:italic>and analyzed thymic and peripheral production and TCR repertoires of naïve conventional CD4<jats:sup>+</jats:sup>T (T<jats:sub>conv</jats:sub>) and naïve regulatory CD4<jats:sup>+</jats:sup>T (T<jats:sub>reg</jats:sub>) cells. Compared with tuberculosis-resistant C57BL/6 (H2-A<jats:sup>b</jats:sup>) mice, the tuberculosis-susceptible H2-A<jats:sup>j</jats:sup>mice had fewer CD4<jats:sup>+</jats:sup>T cells of both subsets in the thymus. In the periphery, this deficiency was only apparent for T<jats:sub>conv</jats:sub>and was compensated for by peripheral reconstitution for T<jats:sub>reg</jats:sub>. We show that H2-A<jats:sup>j</jats:sup>favors selection of a narrower and more convergent repertoire with more hydrophobic and strongly interacting amino acid residues in the middle of CDR3α and CDR3β, suggesting more stringent selection against a narrower peptide–MHC-II context. H2-A<jats:sup>j</jats:sup>and H2-A<jats:sup>b</jats:sup>mice have prominent reciprocal differences in CDR3α and CDR3β features, probably reflecting distinct modes of TCR fitting to MHC-II variants. These data reveal the mechanics and extent of how MHC-II shapes the naïve CD4<jats:sup>+</jats:sup>T cell CDR3 landscape, which essentially defines adaptive response to infections and self-antigens.</jats:p>

Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

“…The two HLA class II molecules presented distinct peptide repertoires and the presentation via HLA-DR15 was associated with the generation of Tconv, while presentation via HLA-DR1 instead led to the development of Tregs that expressed tolerogenic cytokines such as IL-10 and TGF-b (116). Similar conclusions were drawn from a different study where (117). This links the polymorphism in the HLA-DR molecules to the fate of T-cells and differentiation to Tregs and production of IgG4 via IL-10 (118-121).…”

Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

“…Although some distinct features, including high scores for hydrophobicity (low Kidera factor 4) and interaction strength in the Treg CDR3β repertoires, were expected from previous studies in mice ( Bolotin et al, 2017 ; Izraelson et al, 2018 ; Logunova et al, 2020 ; Feng et al, 2015 ), more unanticipated characteristics were identified among other subsets of effector/memory CD4 + T cells ( Figure 2 ). In particular, the Tfh CDR3β repertoires exhibited the lowest averaged scores for hydrophobicity (high Kidera factor 4; Figure 2C ), interaction strength ( Figure 2D ), and volume ( Figure 2F , reflects the number of bulky amino acid residues, namely W, R, K, Y, and F [ Shugay et al, 2015 ]), and the highest averaged score for surface ( Figure 2E , provides an in silico predictive measure of amino acid residues that remain unchanged in terms of accessibility and position in the liganded versus unliganded state [ Martin and Lavery, 2012 ]).…”

“…Statistical analyses of the curated TCRα and TCRβ datasets allowed us to describe the somatically rearranged third complementarity-determining region (CDR3) loops in terms of amino acid representation among distinct subsets of effector/memory CD4 + T cells. As in previous studies ( Bolotin et al, 2017 ; Izraelson et al, 2018 ; Egorov et al, 2018 ; De Simone et al, 2019 ; Logunova et al, 2020 ), we focused on amino acid residues located in the middle of the CDR3 loop, which typically dominate contacts with the peptide component of any cognate pMHC ( Egorov et al, 2018 ), and quantified several key physicochemical properties, including hydrophobicity ( Kidera et al, 1985 ) and the predicted energy of TCR interactions averaged across diverse pMHCs ( Miyazawa and Jernigan, 1996 ; Kosmrlj et al, 2008 ; Kosmrlj et al, 2010 ). This latter parameter provides a generic measure of interaction strength and depends mainly on the prevalence of aromatic and hydrophobic amino acid residues ( Chakrabarti and Bhattacharyya, 2007 ).…”

Engineering a self-navigated MnARK nanovaccine for inducing potent protective immunity against novel coronavirus

“…Thus, the activation of DCs can dramatically facilitate a vaccine’s ability to induce potent T cell responses [40] . Furthermore, we examined the expression of three critical indicators (major histocompatibility complex (MHC) class II molecules (MHC-II), CD69 and CD86) on the surface of B cells to evaluate the maturation of B cells [41] , [42] . B cells from the mouse group receiving the MnARK nanovaccine exhibited a significantly greater expression of MHC-II, CD69 and CD86 than those in the RBD group, indicating that MnARK nanovaccine can promote the maturation of B cells in vivo ( Supplementary Fig.…”