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Machine learning predictions of MHC-II specificities reveal alternative binding mode of class II epitopes

ABSTRACT: CD4+ T cells orchestrate the adaptive immune response against pathogens and cancer by recognizing epitopes presented on MHC-II molecules. The high polymorphism of MHC-II genes represents an important hurdle towards accurate predictions of CD4+ T-cell epitopes in different individuals and different species. Here we generated and curated a dataset of 627,013 unique MHC-II ligands identified by mass spectrometry. This enabled us to determine the binding motifs of 88 MHC-II alleles across human, mouse, cattle and chicken. Analysis of these binding specificities combined with X-ray crystallography refined our understanding of the molecular determinants of MHC-II motifs and revealed a widespread reverse binding mode in MHC-II ligands. We then developed a machine learning framework to accurately predict binding specificities and ligands of any MHC-II allele. This tool improves and expands predictions of CD4+ T-cell epitopes, as demonstrated by the identification of several viral and bacterial epitopes following the aforementioned reverse binding mode.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Michal Bassani-Sternberg

LAB HEAD: Michal Bassani-Sternberg

PROVIDER: PXD034773 | Pride | 2023-04-07

REPOSITORIES: Pride

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			Action	DRS
	20190208_QE_HFX2_LC3_JMI_SA_CM647_HLADP_R01.raw	Raw
	20190208_QE_HFX2_LC3_JMI_SA_CM647_HLADQ_R01.raw	Raw
	20190208_QE_HFX2_LC3_JMI_SA_CM647_HLADR_R01.raw	Raw
	20190208_QE_HFX2_LC3_JMI_SA_CM647_HLAIIp_R01.raw	Raw
	20190314_QE_HFX2_LC3_SA_JMI_3865DM_HLADP_R01.raw	Raw

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Project description:The presence of Donor-Specific anti-HLA Antibodies (DSA) is associated with an increased risk of both acute and chronic antibody-mediated rejection (AMR) in kidney allografts. AMR has remained challenging in kidney transplantation and is the major cause of late allograft loss. However, not all patients with DSA develop AMR, leading to the question of whether this represents accommodation, if other protective mechanisms exist or if this is actually a state of pre-rejection. Clinical and histological features, and gene expression profiles of kidney biopsy and blood samples of donor-specific antibody (DSA)+ patients without rejection were compared to antibody-mediated rejection (AMR) patients to elucidate the mechanisms involved in prevention of AMR. Of the 71 DSA+ patients, 46 had diagnosis of AMR and 25 did not show rejection. 50 DSA- patients without rejection were used as control. A subgroup of patients with available biopsy (n=61) and blood samples (n=54) were analyzed by microarrays. Both, DSA+/AMR+ and DSA+/AMR- biopsies showed increased expression of gene transcripts associated with cytotoxic T, natural killer cells, macrophages, interferon-gamma and rejection compared to DSA- biopsies. Regulatory T cell transcripts were up-regulated in DSA+/AMR+ and B cell transcripts in DSA+/AMR- biopsies. Whole blood gene expression analysis showed increased immune activity in only DSA+/AMR+ patients. There were no differentially expressed tolerant genes studied (n=14) in the blood or biopsy specimens of DSA+/AMR- patients. During a median 36 months follow-up, 4 DSA+/AMR- patients developed AMR, 12 continued to have DSAs but 9 lost DSAs. Gene expression profiles did not predict the development of AMR or persistence of DSAs. These results indicate increased immune activity in DSA+/AMR- biopsies despite lack of histologic findings of rejection. All clinically indicated kidney transplant biopsies performed at our institution after January 2009 were reviewed and 263 patients with anti-HLA antibody testing at the time of biopsy were identified. There were 71 DSA+ and 192 DSA- patients (Figure 1). Of the 71 DSA+ patients, 46 had biopsy diagnosis of acute AMR (n=9) or chronic AMR (n=37), and 25 had normal histopathology or minimal non-specific interstitial fibrosis/tubular atrophy (IFTA). Of the 192 DSA- patients, 50 patients with normal histology and/or mild non-specific IFTA were used as a control group. Clinical and histopathological findings of these 3 groups (DSA+/AMR+, DSA+/AMR- and DSA-) were analyzed. A subgroup of patients who were enrolled in the Institutional Review Board-approved âImmune Monitoring Studyâ who had clinically indicated biopsy (n=61) and whole blood samples (n=54) stored were used for genomic analysis. Twenty-eight biopsy and blood samples from DSA+/AMR+ patients, 13 biopsy and 14 blood samples from DSA+/AMR- patients, and 20 biopsy and 12 blood samples from DSA- patients, were available for microarray analysis.

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Machine learning predictions of MHC-II specificities reveal alternative binding mode of class II epitopes

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