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Joanne Turner, Shalini Gautam, Varun Dwivedi, A mouse model of age-associated tuberculosis reactivation positions KLRG1 as a modulator of disease progression., The Journal of Immunology, Volume 198, Issue Supplement_1, May 2017, Page 131.7, https://doi.org/10.4049/jimmunol.198.Supp.131.7
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Abstract
Tuberculosis (TB) in the elderly can arise from reactivation of M.tb infection that was acquired when younger and immune exhaustion or senescence is thought to play a role in this process. KLRG1 is an inhibitory receptor of T cell function and its expression is elevated on T cells with increasing age and T cell differentiation status. We have previously shown using KLRG1-KO mice that the absence of KLRG1 provides a survival advantage to chronic M.tb infected mice, showing proof of concept for an inhibitory role of this receptor during M.tb infection. We hypothesized that KLRG1 would have a more significant role in a model of age-associated reactivation TB where immuno-senescence can also play a role. We infected young wild type (WT) and KLRG1 KO mice with M.tb and then reduced the M.tb CFU to low levels using the modified Cornell model (2–3 months isoniazid/rifampicin in water), allowing mice to live into old age. Mice were sampled every 2–4 months for determination of TB reactivation and immune function. M.tb CFU were moderately increased in lung and spleen of WT mice around 14 months of age, an age that is associated with shifts in T cell phenotype and function. For WT mice M.tb CFU reached levels similar to a chronic M.tb infection approximately 18–20 months of age. A significant increase in total T cell numbers and antigen specific CD4 T cells in the lung also occurred at that age. In contrast, KLRG1 KO mice had a substantial delay in reactivation of M.tb, indicating that KLRG1 has a functional inhibitory role during M.tb infection. Our data suggest that modulating KLRG1 function, or the development of T cells that express KLRG1, can have beneficial outcome on the susceptibility of the elderly to succumb to reactivation TB.
