Joseph C. Sun

Adaptive immune features of natural killer cells

In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing ‘memory’ NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.

The Immunological Genome Project: networks of gene expression in immune cells

The Immunological Genome Project combines immunology and computational biology laboratories in an effort to establish a complete road map of gene-expression and regulatory networks in all immune cells

Molecular definition of the identity and activation of natural killer cells

Using whole-genome microarray data sets of the Immunological Genome Project, we demonstrate a closer transcriptional relationship between NK cells and T cells than between any other leukocytes, distinguished by their shared expression of genes encoding molecules with similar signaling functions. Whereas resting NK cells are known to share expression of a few genes with cytotoxic CD8+ T cells, our transcriptome-wide analysis demonstrates that the commonalities extend to hundreds of genes, many encoding molecules with unknown functions. Resting NK cells demonstrate a preprimed state compared with naive T cells, which allows NK cells to respond more rapidly to viral infection. Collectively, our data provide a global context for known and previously unknown molecular aspects of NK cell identity and function by delineating the genome-wide repertoire of gene expression of NK cells in various states.Using whole-genome microarray data sets of the Immunological Genome Project, we demonstrate a closer transcriptional relationship between NK cells and T cells than between any other leukocytes, distinguished by their shared expression of genes encoding molecules with similar signaling functions. Whereas resting NK cells are known to share expression of a few genes with cytotoxic CD8(+) T cells, our transcriptome-wide analysis demonstrates that the commonalities extend to hundreds of genes, many encoding molecules with unknown functions. Resting NK cells demonstrate a preprimed state compared with naive T cells, which allows NK cells to respond more rapidly to viral infection. Collectively, our data provide a global context for known and previously unknown molecular aspects of NK cell identity and function by delineating the genome-wide repertoire of gene expression of NK cells in various states.

Natural killer cells remember: An evolutionary bridge between innate and adaptive immunity?

Since their discovery three decades ago, NK cells have been classified as cells of the innate immune system. NK cells were shown to respond rapidly and non‐specifically to infection, and were thought to act as a functional “bridge” to sustain the early innate immune response until the later adaptive immune responses could be mounted. In light of new findings showing how NK cells possess nearly all of the features of adaptive immunity including memory, we propose the placement of NK cells as an “evolutionary bridge” between innate and adaptive immunity.

Tolerance of NK cells encountering their viral ligand during development

During development, T and B cells encountering their cognate ligands via antigen-specific receptors are deleted or rendered anergic. Like T and B cells, natural killer (NK) cells express certain receptors, such as Ly49H, associated with immunoreceptor tyrosine-based activation motif–bearing adaptor proteins that transmit activating signals through Syk family kinases. Ly49H binds with high affinity to a mouse cytomegalovirus (MCMV)–encoded glycoprotein, m157, but does not recognize self-antigens. For comparison with the behavior of immature T and B cells exposed to foreign antigens, we addressed the fate of Ly49H+ NK cells that encountered their viral ligand during development by retroviral transduction of bone marrow stem cells with m157. In chimeric mice expressing m157, we observed a reduction in Ly49H+ NK cells in multiple tissues and less Ly49H on the cell surface. NK cells exposed to m157 during development appeared less mature, produced less interferon γ when stimulated through Ly49H, and were unable to kill m157-bearing target cells. After MCMV infection, these NK cells were severely impaired in their ability to proliferate. Thus, if immature NK cells encounter ligands for their activating receptors, regulatory mechanisms exist to keep these cells in an unresponsive state.

Immune memory redefined: characterizing the longevity of natural killer cells.

Summary:u2002 Natural killer (NK) cells respond rapidly to transformed, stressed, or virally infected cells and provide a first‐line immune defense against pathogen invasion and cancer. Thought to involve short‐lived effector cells that are armed for battle, NK cells were not previously known to contribute in recall responses to pathogen re‐encounter. Here, we highlight recent discoveries demonstrating that NK cells are not limited to driving primary immune responses to foreign antigen but can mount secondary responses contributing to immune memory. We also further characterize the phenotype and function of long‐lived memory NK cells generated during viral infection.

Cutting Edge: Viral Infection Breaks NK Cell Tolerance to “Missing Self”

NK cells attack cells lacking MHC class I, yet MHC class I-deficient mice have normal numbers of NK cells with intact, albeit diminished, functions. Moreover, wild-type NK cells are tolerant of MHC class I-deficient cells in mixed bone marrow chimeras. In this study, we investigated how the absence of MHC class I affects NK cells. NK cells from β2-microglobulin-deficient (B2m−/−) and wild-type mice exhibit similar phenotypic and functional characteristics. Both B2m−/− and wild-type Ly49H+ NK cells proliferated robustly and produced IFN-γ after infection with mouse CMV. NK cells in mixed wild-type:B2m−/− chimeric mice were initially tolerant of MHC class I-deficient host cells. However, this tolerance was gradually lost over time and after mouse CMV infection was rapidly broken, with a pronounced rejection of host B2m−/− hematopoietic cells. Thus, although NK cells can be held in check against “missing self,” acute inflammation driven by infection can rapidly break established self-tolerance.

The Natural Selection of Herpesviruses and Virus-Specific NK Cell Receptors

During the co-evolution of cytomegalovirus (CMV) and natural killer (NK) cells, each has evolved specific tactics in an attempt to prevail. CMV has evolved multiple immune evasion mechanisms to avoid detection by NK cells and other immune cells, leading to chronic infection. Meanwhile, the host has evolved virus-specific receptors to counter these evasion strategies. The natural selection of viral genes and host receptors allows us to observe a unique molecular example of “survival of the fittest”, as virus and immune cells try to out-maneuver one another or for the virus to achieve détente for optimal dissemination in the population.

Do the terms innate and adaptive immunity create conceptual barriers

Lewis Lanier and Joseph Sun suggest that new data showing that innate immune cells can have memory characteristics make a strict binary classification between innate and adaptive immunity meaningless.

Differential requirements for CD45 in NK-cell function reveal distinct roles for Syk-family kinases

The protein tyrosine phosphatase CD45 is an important regulator of Src-family kinase activity. We found that in the absence of CD45, natural killer (NK) cells are defective in protecting the host from mouse cytomegalovirus infection. We show that although CD45 is necessary for all immunoreceptor tyrosine-based activation motif (ITAM)-specific NK-cell functions and processes such as degranulation, cytokine production, and expansion during viral infection, the impact of CD45 deficiency on ITAM signaling differs depending on the downstream function. CD45-deficient NK cells are normal in their response to inflammatory cytokines when administered ex vivo and in the context of viral infection. Syk and ζ chain-associated protein kinase 70 (Zap70) are thought to play redundant roles in transmitting ITAM signals in NK cells. We show that Syk, but not Zap70, controls the remaining CD45-independent, ITAM-specific NK-cell functions, demonstrating a functional difference between these 2 Syk-kinase family members in primary NK cells.