Group 1 ILCs regulate T cell–mediated liver immunopathology by controlling local IL-2 availability

Abstract

Group 1 innate lymphoid cells (ILCs), which comprise both natural killer (NK) cells and ILC1s, are important innate effectors that can also positively and negatively influence adaptive immune responses. The latter function is generally ascribed to the ability of NK cells to recognize and kill activated T cells. Here, we used multiphoton intravital microscopy in mouse models of hepatitis B to study the intrahepatic behavior of group 1 ILCs and their cross-talk with hepatitis B virus (HBV)–specific CD8 + T cells. We found that hepatocellular antigen recognition by effector CD8 + T cells triggered a prominent increase in the number of hepatic NK cells and ILC1s. Group 1 ILCs colocalized and engaged in prolonged interactions with effector CD8 + T cells undergoing hepatocellular antigen recognition; however, they did not induce T cell apoptosis. Rather, group 1 ILCs constrained CD8 + T cell proliferation by controlling local interleukin-2 (IL-2) availability. Accordingly, group 1 ILC depletion, or genetic removal of their IL-2 receptor a chain, considerably increased the number of intrahepatic HBV-specific effector CD8 + T cells and the attendant immunopathology. Together, these results reveal a role for group 1 ILCs in controlling T cell–mediated liver immunopathology by limiting local IL-2 concentration and have implications for the treatment of chronic HBV infection.

Organ-specific response after low-dose interleukin-2 therapy for steroid-refractory chronic graft-versus-host disease

“…By competing for exogenous IL-2, preferential expansion of this NK subset may impair the ability of CD4Treg to expand and promote immune tolerance. 30 …”

IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs

“…These somehow unexpected clinical results observed in liver transplant recipients are reminiscent of what has been described in murine models of intra-hepatic T cell priming, in which IL-2 reverts the inactivation of CD8+ T cells that takes place when they recognize cognate antigens expressed by hepatocytes ( 50 ). Recent data indicate that this process is regulated by NK and ILC1 cells, which constitute a significant proportion of intra-hepatic immune cells and compete with T cells for IL-2 ( 51 ). Altogether, these data indicate that IL-2 administration constitutes a double-edged sword in what regards controlling intra-hepatic inflammation.…”

Transcription factor-driven regulation of ILC1 and ILC3

“…infection-or DSS-elicited colitis, as reviewed recently [53,54]. The protective role of ILC3 during colitis is founded on their ability to express IL2, MHC class II (MHCII), and OX40L, which is relevant for their effect on T cell responses [4][5][6][55][56][57].…”