Comprehensive Analysis of CD4+ T Cell Response Cross-Reactive to SARS-CoV-2 Antigens at the Single Allele Level of HLA Class II

Abstract

Common human coronaviruses have been circulating undiagnosed worldwide. These common human coronaviruses share partial sequence homology with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); therefore, T cells specific to human coronaviruses are also cross-reactive with SARS-CoV-2 antigens. Herein, we defined CD4+ T cell responses that were cross-reactive with SARS-CoV-2 antigens in blood collected in 2016–2018 from healthy donors at the single allele level using artificial antigen-presenting cells (aAPC) expressing a single HLA class II allotype. We assessed the allotype-restricted responses in the 42 individuals using the aAPCs matched 22 HLA-DR alleles, 19 HLA-DQ alleles, and 13 HLA-DP alleles. The response restricted by the HLA-DR locus showed the highest magnitude, and that by HLA-DP locus was higher than that by HLA-DQ locus. Since two alleles of HLA-DR, -DQ, and -DP loci are expressed co-dominantly in an individual, six different HLA class II allotypes can be used to the cross-reactive T cell response. Of the 16 individuals who showed a dominant T cell response, five, one, and ten showed a dominant response by a single allotype of HLA-DR, -DQ, and -DP, respectively. The single allotype-restricted T cells responded to only one antigen in the five individuals and all the spike, membrane, and nucleocapsid proteins in the six individuals. In individuals heterozygous for the HLA-DPA and HLA-DPB loci, four combinations of HLA-DP can be expressed, but only one combination showed a dominant response. These findings demonstrate that cross-reactive T cells to SARS-CoV-2 respond with single-allotype dominance.

Comprehensive analysis of mycobacterium tuberculosis antigen-specific CD4+ T cell responses restricted by single HLA class II allotype in an individual

“…The CD4 + T cell response to M. tuberculosis antigens was higher in HLA-DR than HLA-DQ and HLA-DP in ex vivo ELISPOT ( Figure 2A ), similar to the CD4 + T cell response to CMV-pp65 and SARS-CoV-2 antigens ( 32 , 37 ). The expression of HLA-DR was higher than HLA-DQ and -DP in PBMCs ( 32 ).…”

“…These results suggest that allotype dominance exists despite the use of a mixture of multiple M. tuberculosis antigens. The T cell response to pp65 of CMV and spike, nucleocapsid, and membrane of SARS-Cov-2 also showed the allotype dominance within an individual ( 32 , 33 , 37 ). At early time points after infection, diverse high-affinity clones were stimulated: however, at late time points, a few low-affinity clones predominated in CMV-pp65-specific T cell responses ( 41 , 42 ).…”

Distribution of HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 allele frequencies in patients with COVID-19 bilateral pneumonia in Russians, living in the Chelyabinsk region (Russia)

“…As this SNP was significantly higher in patients who progressed to a severe COVID-19 disease, it might be directly linked to a lower antigen presentation [13] . The presence of the SNP rs9277534A is associated with lower HLA-DP antigen expression; supposedly this might impact the SARS-CoV-2-derived peptide repertoire that antigen presenting cells could process and present to the virus-specific CD4+ T-cells [13] , [25] , [26] .…”

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression

“…The ability to activate CD4+ T cells is restricted to antigen-presenting cells that are endocytosed and processed in lysosomes for presentation on MHC class II molecules, which can transduce signals required for B-cell activation. Moreover, MHC class II antigen presentation by B lymphocytes is a multistep process involving in the presentation of MHC II-peptide complexes to CD4+ T cells ( 44 – 47 ). Although the host’s innate immune system works against the virus particles in this process, a small number of viruses still escape, and the RNAs released by these viruses are captured and identified by toll-like receptors (TLRs).…”

“…As a result, MHC class I contributes towards antiviral immunity by facilitating the presentation of viral antigens to CD8 cytotoxic T cells. Moreover, the ability of antigen-presenting cells to capture external antigens and present them as peptide fragments, loaded on MHC class II molecules, which can transduce signals required for B-cell activation, to CD4+ T cells is a crucial part of the adaptive immune response ( 39 – 47 ). In addition, the RNA released by the virus is captured and recognized by the pattern recognition receptor Toll-like receptor (TLR) located on the endosomal membrane.…”