Immunoregulation: Uncovering the 'brakes' on immune activation
CD4+ and CD8+ T cells have a powerful ability to drive immune activation and promote clearance of infections and cancer. However, their function can also promote deleterious autoimmune and allergic inflammation. The immune system therefore employs a variety of suppressive mechanisms, collectively referred to as immunoregulatory mechanisms, to restrain excessive immune activation. While immunoregulatory mechanisms play a beneficial role in preventing inflammation, they can also powerfully suppress immune responses during chronic infections and cancer in a process referred to as immunosuppression. Immunoregulatory mechanisms therefore function as 'brakes' on immune activation and are important therapeutic targets. Our research aims to understand the molecular and cellular mechanisms of peripheral tolerance and immunosuppression under physiological conditions, and during infection, inflammation and cancer. We hope that this 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.
Nat Rev Immunol. 2017 doi: 10.1038/nri.2017.26.
Ionic immune suppression within the tumour microenvironment limits T cell effector function.
Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Marston Linehan W, Roychoudhuri R, Restifo NP.
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.
Cell. 2016 166:1117-31.
BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers.
Roychoudhuri, R, Clever D, Li P, Wakabayashi Y, Quinn KM, Klebanoff CA, Ji Y, Sukumar M, Eil RL, Yu Z, Spolski R, Palmer DC, Pan JH, Patel SJ, Macallan DC, Fabozzi G, Shih HY, Kanno Y, Muto A, Zhu J, Gattinoni L, O'Shea JJ, Okkenhaug K, Igarashi K, Leonard WJ, Restifo NP.
Nat Immunol. 2016 17:851-60.
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.
J Clin Invest. 2016 126:599-604.
BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.
Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA, Bonelli M, Sciumè G, Zare H, Vahedi G, Dema B, Yu Z, Liu H, Takahashi H, Rao M, Muranski P, Crompton JG, Punkosdy G, Bedognetti D, Wang E, Hoffmann V, Rivera J, Marincola FM, Nakamura A, Sartorelli V, Kanno Y, Gattinoni L, Muto A, Igarashi K, O'Shea JJ, Restifo NP.
Nature. 2013 498:506-10.
Super-enhancers delineate disease-associated regulatory nodes in T cells.
Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ.
Nature. 2015 520:558-62.
Joining the group
Informal enquiries regarding PhD and postdoctoral positions and potential fellowship applications can be made by email and should include details of the applicant's research background and a curriculum vitae.