Mechanisms of tolerance and immunosuppression
CD4+ and CD8+ effector T cells promote immune activation and drive clearance of infections and cancer but their function is restricted by a diverse set of peripheral tolerance mechanisms. While such mechanisms are required to prevent deleterious autoimmune and allergic reactions, they also powerfully suppress immune responses against chronic infections and cancer, preventing immune-mediated rejection of disease.
Our group is interested in understanding the molecular and cellular mechanisms of peripheral tolerance and immunosuppression using a variety of approaches including mouse genetics, cellular and molecular immunology, functional genomics and protein biochemistry. Targeting mechanisms underlying peripheral tolerance and immunosuppression may enable development of new therapies aimed at manipulating immune function in patients with inflammation and cancer.
Transcriptional and epigenetic control of T cell lineage choice
T cells coordinate immune function by differentiating into highly specialised cellular lineages. Whereas effector T cells promote immune activation, regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, suppress their function, preventing excessive autoimmune and allergic reactions. Treg cells therefore represent an important mechanism of peripheral tolerance and stability of Treg populations is required throughout life to prevent lethal inflammation. In cancer, however, regulatory T cells powerfully limit effector responses and their remarkable stability is a barrier to immune-mediated clearance of disease. The choice between effector and regulatory T cell lineage commitment is therefore among the most consequential decisions the immune system has to make. The transcription factor Forkhead box P3 (Foxp3) is required for Treg differentiation, but a broader network of TFs, including the transcriptional repressor BACH2, act early during Foxp3+ regulatory T cell differentiation to guide lineage choice and establish the full Treg cell transcriptional program. We are interested in the transcriptional and epigenetic mechanisms that determine CD4+ T cell lineage choice.
Figure 1. CD4+ T cell lineage choice and mechanisms of peripheral tolerance. CD4+ effector and regulatory T (Treg) cells arise from common precursor cells yet exert dichotomous functions. Treg cells arising in both the thymus and periphery restrain effector cells to promote peripheral tolerance. Peripheral tolerance is also maintained by diverse extrinsic signals present in lymphatic tissues and local tissue microenvironments that function to further limit effector responses.
Molecular and cellular mechanisms of tumour immunosuppression
Growth of tumours in immunocompetent hosts is at odds with the powerful ability of the immune system to recognize and kill cancer cells. The cancer immunoediting hypothesis has been proposed as a conceptual framework to account for this behaviour. According to this hypothesis, tumour development is characterized by an initial ‘elimination’ phase, during which a majority of cancer cells are destroyed by various components of the immune system. This is followed by an ‘equilibrium’ phase, during which pressure from the immune system contributes to selection of tumour variants that give rise to an ‘escape’ phase characterized by evasion from immune control and unrestrained tumour growth. While selection of antigen-loss variants represents a mechanism of tumour escape, it fails to explain why established tumours continue to express immunogenic epitopes that are recognized by tumour-infiltrating lymphocytes. Growth of tumours containing immunogenic epitopes is better explained through an understanding of the critical role of immunosuppression in promoting tumour escape. Several projects in the laboratory aim to investigate the mechanisms by which immune function is suppressed within tumours. In particular, we are focussed on characterising microenvironmental factors and T cell-intrinsic mechanisms of immunosuppression, and adaptations by tumour cells to host immunity.
Figure 2. How is the function of the immune system suppressed during tumour development. Tumour development is characterized by an initial ‘elimination’ phase, during which a majority of cancer cells are destroyed by a variety of components of the innate and adaptive immune systems, including CD8+ T cells and NK cells. This process results, referred to as immunoediting, results in an ‘equilibrium’ phase, during which pressure from the immune system contributes to selection of tumour variants that do not express antigens targeted by the adaptive immune system or have developed mechanisms to suppress immune function. This gives rise to the ‘escape’ phase characterized by recruitment and support of the differentiation and proliferation of immunosuppressive cell types including Treg cells, tumour-associated macrophages and myeloid-derived suppressor cells, expression of inhibitory ligands and such as PD-L1 and production of immunosuppressive factors such as TGF-b resulting in evasion from immune control and unrestrained tumour growth.
Signal integration and contextual control of T cell function by enhancers
Enhancers are distal regulatory elements that bind transcription factors and act in conjunction with promoters to control gene expression. Enhancers can lie at great distances from their target genes and form looping interactions with gene promoters to bring enhancer-bound transcription factor (TF) complexes into contact with general TFs assembled at promoters. Genetic variations associated with autoimmune and allergic diseases are concentrated within enhancers indicating their importance in regulating immune function. Features of enhancers include H3K4me1 and H3K27Ac histone modifications, and p300 binding. Although individual gene isoforms have one promoter, they can have multiple enhancers, the accessibility of which is controlled by lineage-specific epigenetic modifications. This allows for specification of tissue-specific enhancer repertoires. The presence of a different sets of enhancers in distinct cell types allows for generation of cell type-specific transcriptional responses initiated by similar signal-transduction and transcription factor pathways and therefore plays central roles in guiding the functional behaviour of specific cell types. We are interested in studying how epigenetic changes occurring at enhancers during T cell differentiation provide a means for T cells to adopt tolerogenic and immunosuppressive functions.
Figure 3. Control of T cell differentiation and function by enhancers. Analysis of genome-wide transcription factor binding, chromatin modification and DNA accessibility at enhancers enables an understanding of critical mechanisms guiding the differentiation and function of T cells in response to extrinsic signals.
BACH transcription factors in innate and adaptive immunity.
Igarashi K, Kurosaki T, Roychoudhuri R.
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Ionic immune suppression within the tumour microenvironment limits T cell effector function.
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Nature 2016 doi:10.1038/nature19364
Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche.
David Clever, Rahul Roychoudhuri, Michael G. Constantinides, Michael H. Askenase, Madhusudhanan Sukumar, Christopher A. Klebanoff, Robert L. Eil, Heather D. Hickman, Zhiya Yu, Jenny H. Pan, Douglas C. Palmer, Anthony T. Phan, John Goulding, Luca Gattinoni, Ananda W. Goldrath, Yasmine Belkaid, Nicholas P. Restifo.
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The transcription factor BACH2 promotes tumor immunosuppression.
Roychoudhuri R, Eil RL, Clever D, Klebanoff CA, Sukumar M, Grant F, Yu Z, Mehta G, Liu H, Jin P, Ji Y, Palmer DC, Pan JH, Chichura A, Crompton JG, Patel SJ, Stroncek D, Wang E, Marincola FM, Okkenhaug K, Gattinoni L, Restifo NP.
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BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.
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Nature. 2013 498:506-10.
Super-enhancers delineate disease-associated regulatory nodes in T cells.
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Nature. 2015 520:558-62.