Immunology

Immature B cells are subject to tolerance mechanisms that prevent the expression of self-reactive BCRs. Minguet and colleagues identify the membrane protein caveolin-1 as a regulator of BCR spatial organization and signaling that enforces B cell tolerance.

Primary immunodeficiencies (PIDs) are genetic disorders impairing host immunity, leading to life-threatening infections, autoimmunity, and/or malignancies. Genomic technologies have been critical for expediting the discovery of novel genetic defects underlying PIDs, expanding our knowledge of the complex clinical phenotypes associated with PIDs, and in shifting paradigms of PID pathogenesis. Once considered Mendelian, monogenic, and completely penetrant disorders, genomic studies have redefined PIDs as a heterogeneous group of diseases found in the global population that may arise through multigenic defects, non-germline transmission, and with variable penetrance. This review examines the uses of NGS in the diagnosis of PIDs. While whole genome sequencing identifies variants throughout the genome, whole exome sequencing sequences only the protein-coding regions within a genome, and targeted gene panels sequence only a specific cohort of genes. The advantages and limitations of each sequencing approach are compared. The complexities of variant interpretation and variant validation remain the major challenge in wide-spread implementation of these technologies. Lastly, the roles of NGS in newborn screening and precision therapeutics for individuals with PID are also addressed.

Author summary IL-7 is important for the development and homeostasis of T cells and promotes antigen-specific T-cell responses. Aberrant expression of plasma IL-7 and soluble IL-7R are found in autoimmune diseases and chronic viral infections. In AIDS patients—especially those who fail to reconstitute T-cell numbers during therapy—impaired IL-7-promoted T-cell functions indicated T-cell exhaustion/senescence. In order to evaluate the potential impact of IL-7 on tuberculosis, we characterised various parameters involved in the IL-7-response of tuberculosis patients and healthy contacts. Despite IL-7 being available at higher plasma levels among tuberculosis patients, the T-cell response to IL-7 was impaired when compared to healthy contacts. Soluble IL-7R levels were aberrantly low in plasma during acute tuberculosis but did not account for impaired IL-7 usage. Chronic inflammation in tuberculosis patients—reflected by increased IL-6 plasma levels—did not account for dysfunctional T-cell responses and analysed T-cell exhaustion markers were only moderately correlated. Our findings demonstrate that availability of IL-7 alone is not sufficient to promote protective T-cell immunity against tuberculosis. We describe aberrant IL-7/soluble IL-7R expression and impaired IL-7-mediated T-cell functions in tuberculosis patients with similarities and differences to described IL-7 dysregulation seen in patients with AIDS.

Specialized populations of regulatory T cells inhabit tissues and maintain homeostasis, and assist with repair functions there. Feuerer and colleagues identify a genome-wide DNA-methylation landscape to define this specialized subset of cells.

Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function. Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation, whether metabolism might control T-cell fate by an epigenetic mechanism is unclear. Here, through the discovery and mechanistic characterization of a small molecule, (aminooxy)acetic acid, that reprograms the differentiation of T helper 17 (TH17) cells towards induced regulatory T (iTreg) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating TH17 cells. The accumulation of 2-hydroxyglutarate resulted in hypermethylation of the Foxp3 gene locus and inhibited Foxp3 transcription, which is essential for fate determination towards TH17 cells. Inhibition of the conversion of glutamate to α-ketoglutaric acid prevented the production of 2-hydroxyglutarate, reduced methylation of the Foxp3 gene locus, and increased Foxp3 expression. This consequently blocked the differentiation of TH17 cells by antagonizing the function of transcription factor RORγt and promoted polarization into iTreg cells. Selective inhibition of GOT1 with (aminooxy)acetic acid ameliorated experimental autoimmune encephalomyelitis in a therapeutic mouse model by regulating the balance between TH17 and iTreg cells. Targeting a glutamate-dependent metabolic pathway thus represents a new strategy for developing therapeutic agents against TH17-mediated autoimmune diseases.

Collaborate with peers to update, evolve and improve the cancer–immune set point framework

The genetic factors associated with susceptibility or resistance to viral infections are likely to involve a sophisticated array of immune-response. These genetic elements may modulate other biological factors that account for significant influence on the gene expression and/or protein function in the host. Among them, the role of the Major Histocompatibility Complex (MHC) in viral pathogenesis in particular HIV and HCV, is very well documented. We recently added a novel insight into the field by identifying the molecular mechanism associated with the protective role of HLA-B27/B57 CD8+ T cells in the context of HIV-1 infection and why these alleles act as a double-edged sword protecting against viral infections but predisposing the host to autoimmune diseases. The focus of this review will be reexamining the role of classical and non-classical HLA-alleles including class Ia (HLA-A, -B, -C), class Ib (HLA-E, -F, -G, -H) and class II (HLA-DR, -DQ, -DM, and -DP) in immune regulation and viral pathogenesis (e.g. HIV and HCV). To our knowledge this is the very first review of its kind to comprehensively analyze the role of these molecules in immune regulation associated with chronic viral infections.