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During the past 15,000 years, Mycobacterium tuberculosis (Mtb) has evolved into a potent human pathogen that avoids elimination and exploits our immune responses for its transmission. While most people control Mtb, immunity fails in 10% of infected people, resulting in 10 million new TB cases and 1.5 million deaths per year. Why immunity fails and leads to clinical disease is an important knowledge gap. Our long-term goal is to inform the development of effective vaccines by understanding the drivers of immune failure and identifying protective mechanisms of immunity to Mtb. While the quantitative balance between successful immunity and failure varies between animal models and people, all have features of immune control and bacterial escape. Mice clear most bacteria after the onset of T cell immunity but fail to sterilize the lung. While T cells are essential to clear bacteria, even highly activated T cells confer only partial protection. We hypothesize that Mtb persist because of a failure in immune surveillance and inhibition of T cell immunity.

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