Life Sciences Research for Lifelong Health

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Rahul Roychoudhuri

Transcriptional regulation of T cell differentiation

T cells coordinate immune function by differentiating into highly specialised cellular lineages. Whereas effector CD4+ and CD8+ T cells promote immune activation and drive clearance of infections and cancer, CD4+ regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, suppress their function, preventing excessive autoimmune and allergic reactions. The suppressive function of Treg cells also powerfully prevents immune responses against cancer. 
 
 
Effector cells and regulatory T cells arise from common precursors yet establish dichotomous function. How is this dichotomous functional programme established and maintained?​

We are interested in understanding general principles and specific mechanisms by which the process of gene expression is controlled within T cells. We hope to apply this knowledge to better understand how the function of the immune system is regulated under physiological conditions, and how the immune system can be manipulated in autoimmunity, infections and cancer. The laboratory employs a variety of techniques including mouse genetics, cellular and molecular immunology, functional genomics and protein biochemistry.


Key publications

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 can be made by email and should include details of the applicant's research background and a curriculum vitae.
 
We are currently accepting applications for the following PhD studentships in the lab: 
 PhD studentship 
Understanding molecular mechanisms of CD4+ T cell differentiation
Supervisor(s): Dr R Rahul Roychoudhuri
Application Deadline: January 2017

Latest Publications

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, Linehan WM, Roychoudhuri R, Restifo NP

Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K(+)]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated [K(+)]e is independent of changes in plasma membrane potential (Vm), it requires an increase in intracellular potassium ([K(+)]i). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv1.3 lowers [K(+)]i and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.

+ View Abstract

Nature, 537, 1476-4687, 539-543, 2016

PMID: 27626381

Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche.
Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, Palmer DC, Phan AT, Goulding J, Gattinoni L, Goldrath AW, Belkaid Y, Restifo NP

Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4(+)-regulatory T (Treg) cell induction, and restrain CD8(+) T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary Treg cells and suppression of IFN-γ-dependent tumor clearance. T-cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. PAPERCLIP.

+ View Abstract

Cell, 166, 1097-4172, 1117-1131.e14, 2016

PMID: 27565342

Identification of novel regulators of developmental hematopoiesis using endoglin regulatory elements as molecular probes.
Nasrallah R, Fast EM, Solaimani P, Knezevic K, Eliades A, Patel R, Thambyrajah R, Unnikrishnan A, Thoms J, Beck D, Vink CS, Smith A, Wong J, Shepherd M, Kent D, Roychoudhuri R, Paul F, Klippert J, Hammes A, Willnow T, Göttgens B, Dzierzak E, Zon LI, Lacaud G, Kouskoff V, Pimanda JE

Enhancers are the primary determinants of cell identity and specific promoter/enhancer combinations of Endoglin (ENG) have been shown to target blood and endothelium in the embryo. Here, we generated a series of embryonic stem cell lines, each targeted with reporter constructs driven by specific promoter/enhancer combinations of ENG, to evaluate their discriminative potential and value as molecular probes of the corresponding transcriptome. The Eng promoter (P) in combination with the -8/+7/+9kb enhancers, targeted cells in FLK1 mesoderm that were enriched for blast colony forming potential, whereas the P/-8kb enhancer targeted TIE2+/c-KIT+/CD41- endothelial cells that were enriched for hematopoietic potential. These fractions were isolated using reporter expression and their transcriptomes profiled by RNA-seq. There was high concordance between our signatures and those from embryos with defects at corresponding stages of hematopoiesis. Of the six genes that were up-regulated in both hemogenic mesoderm and hemogenic endothelial fractions targeted by the reporters, LRP2, a multiligand receptor, was the only gene that had not previously been associated with hematopoiesis. We show that LRP2 is indeed involved in definitive hematopoiesis and by doing so validate the use of reporter gene coupled enhancers as probes to gain insights into transcriptional changes that facilitate cell fate transitions.

+ View Abstract

Blood, , 1528-0020, , 2016

PMID: 27554085

 

Group Members

Latest Publications

Ionic immune suppression within the tumour microenvironment limits T cell effector function.

Eil R, Vodnala SK, Clever D

Nature
537 1476-4687:539-543 (2016)

PMID: 27626381

Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche.

Clever D, Roychoudhuri R, Constantinides MG

Cell
166 1097-4172:1117-1131.e14 (2016)

PMID: 27565342

BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers.

Roychoudhuri R, Clever D, Li P

Nature immunology
1529-2916: (2016)

PMID: 27158840

The transcription factor BACH2 promotes tumor immunosuppression.

Roychoudhuri R, Eil RL, Clever D

The Journal of clinical investigation
1558-8238: (2016)

PMID: 26731475

Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy.

Sukumar M, Liu J, Mehta GU

Cell metabolism
1932-7420: (2015)

PMID: 26674251

Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy.

Klebanoff CA, Scott CD, Leonardi AJ

The Journal of clinical investigation
1558-8238: (2015)

PMID: 26657860

Oncogenic PI3Kα promotes multipotency in breast epithelial cells.

Okkenhaug K, Roychoudhuri R

Science signaling
8 1937-9145:pe3 (2015)

PMID: 26535006

Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape.

Crompton JG, Narayanan M, Cuddapah S

Cellular & molecular immunology
2042-0226: (2015)

PMID: 25914936

The interplay of effector and regulatory T cells in cancer.

Roychoudhuri R, Eil RL, Restifo NP

Current opinion in immunology
33C 1879-0372:101-111 (2015)

PMID: 25728990

Super-enhancers delineate disease-associated regulatory nodes in T cells.

Vahedi G, Kanno Y, Furumoto Y

Nature
1476-4687: (2015)

PMID: 25686607