Tolerance and exhaustion: defining mechanisms of T cell dysfunction

• Exhaustion and tolerance represent distinct CD8 T cell differentiation states.
• These distinct states are associated with unique molecular programs.
• Exhaustion and tolerance are not fixed, but flexible and plastic cell states.
• Certain characteristics are epigenetically imprinted and independent from external cues.

CD8 T cell activation and differentiation are tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional states have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with an emphasis on: (i) T cell tolerance to self-antigens (self-tolerance); (ii) T cell exhaustion during chronic infections; and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal.