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Science


Tuberculosis
​TB is a major cause of global morbidity and mortality, killing up to 1.5 million people every year. Despite tremendous progress in our understanding of TB, infections are increasing, multidrug resistant bacterial strains are on the rise, and impoverished people with little access to long, expensive treatments continue to bear the brunt of disease. The only existing vaccine against TB was developed 100 years ago and is largely ineffective in certain populations and against pulmonary TB. The largest barrier to development of an effective TB vaccine is our failure to understand the fundamental characteristics of a protective immune response.
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TCR signal strength and infection
​There is an ongoing debate about whether the strength of T cell receptor (TCR) signals alone can independently instruct one Th cell fate over another.  Over the years, work around this question has expanded to address the impact of TCR stimulation on the development of TFH cells, with often conflicting results.  Many of these discrepancies might boil down to the model systems used to investigate T cell differentiation, including different types of TCR transgenic strains/peptide variants, immunization versus infection, etc.  Importantly, although cumulative TCR signal strength is influenced by the cellular microenvironment, whether or not TCR signal strength plays a primary role in CD4 T cell fate decisions occurring within distinct infectious contexts is unknown.  To address this, we generated a panel of variant viruses by introducing mutations into the immunodominant peptide of both acute and chronic strains of lymphocytic choriomeningitis virus.
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CD4 TRM heterogeneity in the lung
To investigate tissue specific T cell responses, we established an influenza model where infection is largely restricted to the lung.  By characterizing the dynamics and transcriptional regulation of lung resident and lymphoid CD4 T cells we defined a “universal” residency signature which is agnostic to Th cell subset; using extensive secondary data analysis we confirmed that this signature is conserved across multiple tissues and infection models.
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TFH cells - the condemned live longer
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Much of the research on CD4 T cell memory is focused on the induction of T central memory (TCM) cells, which due to their persistence and multipotency have long been considered an optimal target for vaccination.  In contrast, T follicular helper (TFH) cells, specialized to support antibody production by B cells, are thought to be short-lived, disappearing within one to two months after viral clearance.  We recently reported that TFH cells are exquisitely sensitive to death induced by extracellular NAD which is released during cell isolation from tissues.  By treating mice with a nanobody to inhibit NAD-induced cell death we found that TFH cells comprise a robust portion of the memory cell compartment, are metabolically fit, and survive to at least 400 days after infection. 

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