Distinct Host–Mycobacterial Pathogen Interactions between Resistant Adult and Tolerant Tadpole Life Stages of Xenopus laevis

Abstract

<i>Mycobacterium marinum</i> is a promiscuous pathogen infecting many vertebrates, including humans, whose persistent infections are problematic for aquaculture and public health. Among unsettled aspects of host–pathogen interactions, the respective roles of conventional and innate-like T (iT) cells in host defenses against <i>M. marinum</i> remain unclear. In this study, we developed an infection model system in the amphibian <i>Xenopus laevis</i> to study host responses to <i>M. marinum</i> at two distinct life stages, tadpole and adult. Adult frogs possess efficient conventional T cell–mediated immunity, whereas tadpoles predominantly rely on iT cells. We hypothesized that tadpoles are more susceptible and elicit weaker immune responses to <i>M. marinum</i> than adults. However, our results show that, although anti–<i>M. marinum</i> immune responses between tadpoles and adults are different, tadpoles are as resistant to <i>M. marinum</i> inoculation as adult frogs. <i>M. marinum</i> inoculation triggered a robust proinflammatory CD8⁺ T cell response in adults, whereas tadpoles elicited only a noninflammatory CD8 negative- and iT cell–mediated response. Furthermore, adult anti–<i>M. marinum</i> responses induced active granuloma formation with abundant T cell infiltration and were associated with significantly reduced <i>M. marinum</i> loads. This is reminiscent of local CD8⁺ T cell response in lung granulomas of human tuberculosis patients. In contrast, tadpoles rarely exhibited granulomas and tolerated persistent <i>M. marinum</i> accumulation. Gene expression profiling confirmed poor tadpole CD8⁺ T cell response, contrasting with the marked increase in transcript levels of the anti–<i>M. marinum</i> invariant TCR rearrangement (<i>iVα45-Jα1.14</i>) and of CD4. These data provide novel insights into the critical roles of iT cells in vertebrate antimycobacterial immune response and tolerance to pathogens.