MHC class I-associated peptides derive from selective regions of the human genome.

MHC class I-associated peptides (MAPs) define the immune self for CD8+ T lymphocytes and are key targets of cancer immunosurveillance. Here, the goals of our work were to determine whether the entire set of protein-coding genes could generate MAPs and whether specific features influence the ability of discrete genes to generate MAPs. Using proteogenomics, we have identified 25,270 MAPs isolated from the B lymphocytes of 18 individuals who collectively expressed 27 high-frequency HLA-A,B allotypes. The entire MAP repertoire presented by these 27 allotypes covered only 10% of the exomic sequences expressed in B lymphocytes. Indeed, 41% of expressed protein-coding genes generated no MAPs, while 59% of genes generated up to 64 MAPs, often derived from adjacent regions and presented by different allotypes. We next identified several features of transcripts and proteins associated with efficient MAP production. From these data, we built a logistic regression model that predicts with good accuracy whether a gene generates MAPs. Our results show preferential selection of MAPs from a limited repertoire of proteins with distinctive features. The notion that the MHC class I immunopeptidome presents only a small fraction of the protein-coding genome for monitoring by the immune system has profound implications in autoimmunity and cancer immunology.

Impact of genomic polymorphisms on the repertoire of human MHC class I-associated peptides.

For decades, the global impact of genomic polymorphisms on the repertoire of peptides presented by major histocompatibility complex (MHC) has remained a matter of speculation. Here we present a novel approach that enables high-throughput discovery of polymorphic MHC class I-associated peptides (MIPs), which play a major role in allorecognition. On the basis of comprehensive analyses of the genomic landscape of MIPs eluted from B lymphoblasts of two MHC-identical siblings, we show that 0.5% of non-synonymous single nucleotide variations are represented in the MIP repertoire. The 34 polymorphic MIPs found in our subjects are encoded by bi-allelic loci with dominant and recessive alleles. Our analyses show that, at the population level, 12% of the MIP-coding exome is polymorphic. Our method provides fundamental insights into the relationship between the genomic self and the immune self and accelerates the discovery of polymorphic MIPs (also known as minor histocompatibility antigens).

MHC I-associated peptides preferentially derive from transcripts bearing miRNA response elements.

MHC I-associated peptides (MIPs) play an essential role in normal homeostasis and diverse pathologic conditions. MIPs derive mainly from defective ribosomal products (DRiPs), a subset of nascent proteins that fail to achieve a proper conformation and the physical nature of which remains elusive. In the present study, we used high-throughput proteomic and transcriptomic methods to unravel the structure and biogenesis of MIPs presented by HLA-A and HLA-B molecules on human EBV-infected B lymphocytes from 4 patients. We found that although HLA-different subjects present distinctive MIPs derived from different proteins, these MIPs originate from proteins that are functionally interconnected and implicated in similar biologic pathways. Secondly, the MIP repertoire of human B cells showed no bias toward conserved versus polymorphic genomic sequences, were derived preferentially from abundant transcripts, and conveyed to the cell surface a cell-type-specific signature. Finally, we discovered that MIPs derive preferentially from transcripts bearing miRNA response elements. Furthermore, whereas MIPs of HLA-disparate subjects are coded by different sets of transcripts, these transcripts are regulated by mostly similar miRNAs. Our data support an emerging model in which the generation of MIPs by a transcript depends on its abundance and DRiP rate, which is regulated to a large extent by miRNAs.

Origin and plasticity of MHC I-associated self peptides.

Endogenous peptides presented by MHC I molecules represent the essence of self for CD8 T lymphocytes. These MHC I peptides (MIPs) regulate all key events that occur during the lifetime of CD8 T cells. CD8 T cells are selected on self-MIPs, sustained by self-MIPs, and activated in the presence of self-MIPs. Recently, large-scale mass spectrometry studies have revealed that the self-MIP repertoire is more complex and plastic than previously anticipated. The composition of the self-MIP repertoire varies from one cell type to another and can be perturbed by cell-intrinsic and -extrinsic factors including dysregulation of cellular metabolism and infection. The complexity and plasticity of the self-MIP repertoire represent a major challenge for the maintenance of self tolerance and can have pervasive effects on the global functioning of the immune system.

Influence of climatic conditions on the isolation of members of the Cryptococcus neoformans species complex from trees in Colombia from 1992-2004.

The aim of this retrospective study was to analyze the relationship between occurrence of the serotypes of the Cryptococcus neoformans species complex in tree samples and the climatic conditions registered during samplings in four cities of Colombia, between 1992 and 2004, by means of a logistic regression model and lagged Pearson correlations. During 97 collection dates, 8220 samples from different tree species were taken, of which 2.63% were positive: 56.5% yielded serotype B, 24.7% serotype C and 18.8% serotype A isolates. The prevalence of the serotypes varied among the cities. The results suggest that environmental climatic conditions, mainly humidity, temperature, evaporation and solar radiation, can affect the occurrence of the different serotypes in trees in a differential manner. These different climatic tolerances were reflected in the geographic distribution of the serotypes in Colombia. The climatic conditions for 15 days before the sampling date were correlated with positive or negative isolation of the different serotypes.