A spectrum of immune memory

Immune memory occurs when the immune system remembers previous encounters with pathogens, aberrant cells, or self-antigens to produce a more rapid or robust secondary response upon re-encounter.  It stands as the cornerstone of vaccine development and many cellular immunotherapies, and is largely believed to be an exclusive capability of conventional T and B cells.  The natural killer (NK) cell, a cytotoxic innate lymphocyte, has challenged these dogmas.

 

Our research aims to leverage the unique ability of NK cells to acquire adaptive features in order to explore immune memory in the context of classic antigen-dependent and more unconventional antigen-independent memory responses. We combine multi-omic approaches with genetic mouse model systems to interrogate in vivo, in vitro, and in silico how different signals integrate to generate an immune memory program.

Common and distinct mechanisms that dictate classic immune memory responses

We have previously shown that NK cells and CD8 T cells have similar epigenetic features in response to mouse cytomegalovirus. We are exploring the role of several transcription factors and epigenetic features that may have common or distinct functionalities in these cells.

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Studies in mouse cytomegalovirus (MCMV) infection has demonstrated that NK cells are capable of exhibiting memory features that resemble the classic antigen-specific responses of the adaptive immune system conferred by T and B cells. Upon the specific engagement of the MCMV-encoded glycoprotein m157 by activating receptor Ly49H on NK cells, NK cells expand, contract, and generate a long-lived pool of memory cells that can be recalled. Within the same mouse model system, MCMV-specific CD8 T cells undergoing similar kinetics can also be tracked via their recognition of MCMV epitope M45. 

Like T cells, Ly49H+ NK cells exhibit similar requirements for activation, which include receptor activation (signal 1), co-stimulation (signal 2), and cytokine regulation (signal 3). We further show that commonalities exist at an epigenetic level by looking at their profiles of chromatin accessibility (Lau et al, 2018). We are interested in the common and distinct factors downstream of these signals, and how they affect the epigenetic and transcriptional landscape during memory formation and function. 

Epigenetic mechanisms that drive antigen-independent immune memory responses

NK cells have the ability to acquire memory-like features upon seeing IL-12, IL-18, and IL-15 simultaneously. We aim to explore how these cytokines translate into epigenetic mechanisms that help rewire these NK cells to become better and more long-lived.

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Aside from antigen-specific memory responses, NK cells can also elicit antigen-independent memory responses via cytokine signaling. These NK cells, termed cytokine-induced memory-like (CIML) NK cells, arise from pre-activation with IL-12 + IL-18 + IL-15, retain a non-specific enhanced capacity to produce IFN-γ upon re-stimulation with cytokines or target cells, and are currently being tested in the clinic. The enhanced capacity for IFN-γ production is associated with demethylation near the Ifng locus, demonstrating that pre- activation can confer some form of epigenetic imprinting. Accordingly, we have previously shown that short- term culture with IL-12 + IL-18 mediates extensive chromatin remodeling, beyond just the Ifng locus. We have further demonstrated that IL-12 + IL-18 signaling can globally cooperate with IL-2 + IL-15 to promote transcriptional and epigenetic changes (Wiedemann et al, 2021). We aim to explore the extent and the mechanisms of epigenetic reprogramming that may underlie these cytokine-induced memory responses.