Increased numbers and suppressive activity of regulatory CD25+CD4+ T lymphocytes in the absence of CD4 engagement by MHC class II molecules

Shen, Xiaoli; Niu, Chun Feng; König, Rolf

doi:10.1016/j.cellimm.2013.05.002

Cited by 2 publications

(1 citation statement)

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“…The only known and established interaction in this domain was that with the coreceptor CD4, and conflicting interpretations exist to this day regarding its mode of interaction, i.e., whether the MHC II molecule was in an ab monomeric form or an (ab) 2 homodimeric form (35,45,58,59). The data in the mouse I-A molecule showed evidence in favor of a homodimer of heterodimers for CD4 coreceptor binding and subsequent T-cell activation (58,60,61), and the CD4-MHC II interaction in the mouse was of far lower affinity than in the human system; thus, one critical experiment concerning this issue might be mutagenesis of all the putative CD4 contact residues in the respective two ab surfaces of the HLA-DR/DQ (ab) 2 homodimer that may act as the CD4 receptors (58,59,62,63). One of course could not eliminate a priori the possibility of a single charged residue, among the residues presuming to participate in the homodimer formation, mediating the most crucial of several residue-residue interactions, as in the case of the CD2-CD48 interaction (64).…”

Section: Discussionmentioning

confidence: 99%

Motifs of Three HLA-DQ Amino Acid Residues (α44, β57, β135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children

et al. 2020

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HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next-generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1- to 18 year-old patients (n = 962) and control subjects (n = 636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically organized haplotype (HOH) association analysis allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues α44Q (odds ratio [OR] 3.29, P = 2.38 * 10−85) and β57A (OR 3.44, P = 3.80 * 10−84) to be associated with T1D in the DQ8/9 cluster representing all ten residues (α22, α23, α44, α49, α51, α53, α54, α73, α184, β57) due to complete linkage disequilibrium (LD) of α44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found α44C and β135D to share the risk for T1D (OR 2.10, P = 1.96 * 10−20). The motif “QAD” of α44, β57, and β135 captured the T1D risk association of DQ8.1 (OR 3.44, P = 3.80 * 10−84), and the corresponding motif “CAD” captured the risk association of DQ2.5 (OR 2.10, P = 1.96 * 10−20). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56, P = 6.35 * 10−8) but negatively with IA-2A (OR 0.59, P = 6.55 * 10−11). QAD was negatively associated with GADA (OR 0.88; P = 3.70 * 10−3) but positively with IA-2A (OR 1.64; P = 2.40 * 10−14), despite a single difference at α44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AAs (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.

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