SummaryThe C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRγδ+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.
Background PARV4 is a human parvovirus first detected and cloned from an individual with a HIV seroconversion-like illness and which subsequently persists in lymphoid tissue and bone marrow. In contrast to B19V, PARV4 infections are most frequently detected in injecting drug users (IDUs), particularly those co-infected with HIV-1. To investigate its transmission routes and whether infections are acquired through plasma-derived blood products, we developed a novel anti-PARV4 ELISA to determine seroprevalence in parenterally exposed and non-exposed subjects. Methods PARV4 VP2 was expressed and used as antigen in an indirect ELISA to detect anti-PARV4 IgG. Results All 50 non-parenterally exposed adult controls were anti-PARV4 negative, in contrast to 67% and 33% antibody frequencies in HIV-positive and –negative IDUs respectively. Predominantly parenteral transmission was confirmed by the finding of similar infection frequencies (11/20 and 4/15) among HIV-coinfected and –uninfected haemophiliacs treated with non-virally inactivated FVIII/IX, whereas all but one of their 35 non-haemophiliac siblings were seronegative (despite close household contact). Conclusions This study provides convincing evidence that PARV4 is primarily transmitted parenterally. Evidence for widespread infection of haemophiliacs treated with non-virally inactivated clotting factor creates fresh safety concerns for plasma-derived blood products, particularly as parvoviruses are relatively resistant to virus inactivation.
Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics.
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