CD4 T cells are important in protection against M. tuberculosis reinfection in cynomolgus macaques

Abstract

Abstract Early human studies show individuals with latent M. tuberculosis (Mtb) infection are less likely to develop active tuberculosis (TB) compared to naïve individuals with similar levels of exposure. Using Mtb-barcoded libraries (Lib A as first and Lib B as second infection), we published that an existing Mtb infection in cynomolgus macaques protects against the establishment and progression of a second Mtb challenge. CD4 T cells are important in control of TB, and depletion results in worse acute infection and latent TB reactivation in macaques. We hypothesized that CD4 T cells play a major role in protection against a secondary Mtb challenge. To test this hypothesis, CD4 T cells were depleted in infected and treated macaques before a second Mtb challenge. As controls, one group received IgG and a naive group received only Lib B. The number of Lib B granulomas in the IgG group was significantly fewer than in the naïve group, while the αCD4 group was in between the two. The IgG group had the lowest lung bacterial burden followed by the αCD4 group (16-fold higher than IgG) and lastly the naïve group (57.5-fold higher than IgG). Both reinfected groups (αCD4 and IgG) had a higher frequency of CD8 T cells producing IFNγ and/or TNF in Lib B granulomas compared to naïve macaques but there was no significant difference when compared to each other. Because each Mtb bacterium has a unique barcode, we can track the spread of Mtb to different organs. Both naïve and αCD4 groups had a greater number of unique Lib B barcodes in the thoracic lymph nodes compared to the IgG group. These data suggest that CD4 T cells help limit the establishment, progression and dissemination of the second infection. However, they are not the only factor responsible for protection against reinfection.