Mycobacterium chelonae sensitisation induces CD4⁺‐mediated cytotoxicity against BCG

Abstract

Significant variability in efficacy of live Mycobacterium bovis BCG as a tuberculosis vaccine is observed globally. Effects of pre-vaccination sensitisation to non-tuberculous environmental mycobacteria (Env) are suspected to underlie this phenomenon, but the mechanisms remain unclear. We postulated that it could be due to Env-specific T cells exerting cytotoxicity against BCG-infected host cells. After murine sensitisation with heat-killed antigens of different Env species, splenocytes from M. chelonae (CHE)-sensitised mice exerted the strongest cytotoxicity against autologous BCG-infected macrophages. This cytotoxicity was correlated with reduced BCG viability. The cytotoxicity was reduced by the depletion of CD4 1 , but not CD8 1 or CD56 1 cells, and CD4 1 cells showed higher percentage of cytotoxicity than CD4 À cells, supporting a role for CD4 1 cells in CHEinduced, BCG-specific cytotoxicity. Additionally, this cytotoxicity was IFN-c, perforin and FasL dependent. After CHE-sensitisation and subsequent BCG intranasal infection, there was significant expansion of lung CD4 1 cells, the main cell type producing IFN-c. This was associated with 2-and 6-fold reductions in lung BCG counts 1 and 3 wk, respectively postinfection, relative to non-sensitised mice. This is the first report describing cytotoxicity against BCG-infected cells as a mechanism underlying the influence of Env sensitisation on subsequent BCG responses.Key words: Bacterial infections . CD4 T cells . Cytotoxicity . Host-pathogen interactions .Immune responses Supporting Information available online IntroductionThe protective efficacy of Mycobacterium bovis BCG against tuberculosis (TB) varies in clinical trials from 0 to 80% [1]. Several trials showing no protection were conducted in developing countries with high TB incidence; among these are many tropical regions where environmental mycobacteria (Env) are prevalent [2] and human immune exposure to Env is high [3]. Among hypotheses proposed for the variability in BCG efficacy [4,5], those invoking the influence of Env exposure on immune modulation of the BCG response are most widely studied and supported [3,[6][7][8]. Env are free-living members of the Mycobacterium genus, dwelling in the soil and open waters, and many species are genetically closely related to BCG (average495% similarity) [9,10]. Palmer first observed in guinea pigs [11] that Env exposure may confer some immune protection against TB, masking the effects of subsequent BCG vaccination. This was later also [6,13]. This may be due to cross-reactive memory responses to shared antigens, but the nature of Env-induced effector cells and how they interact subsequently with BCG-infected cells, were not described in those studies.There is evidence for human T cells with mycobacteriumspecific cytotoxic activity [14] and that mycobacteria can be killed via cytotoxicity mechanisms [15,16]. Cytotoxicity against mycobacterium-infected cells may be influenced by . Therefore, we hypothesised that the curtailment of BCG survival after Env exposu...

Regulatory T cells induced by Mycobacterium chelonae sensitization influence murine responses to bacille Calmette-Guérin

“…2A). In our previous work [9], however, we had shown that post-BCG-splenic IFN-␥ production by ELISA was similar between sensitized and nonsensitized mice. Splenic IL-10 concentrations were lower 3 weeks after BCG administration (Fig.…”