T Cell Interaction Lab

A defining feature of immunity is the acquisition and maintenance of immunological memory, which confers enhanced protection against pathogens.

Exploiting this, vaccine development has saved the lives of millions worldwide. Despite successes, considerable challenges remain for the development of vaccines against a number of recalcitrant viral infections of global importance.

This study investigates the cellular players and interactions that determine fate T cell fate decisions between effector and memory formation and will reveal how cellular positioning influences the maintenance and function of memory responses.

Project resources:
Duckworth DC, Lafouresse F, Wimmer VC, Broomfield BJ, Alexandre YO, Sheikh AA, Qin RZ, Alvarado C, Mielke LA, Pellegrini M, Mueller SN, Boudier T, Rogers KL, Groom JR. Effector and stem-like memory cell fates are imprinted in distinct lymph node niches directed by CXCR3 ligands. Nat Immunol 2021 Apr;22(4):434-448. PMID: 33649580

Duckworth BC, Groom JR. Conversations that count: Cellular interactions that drive T cell fate. Immunol Rev 2021 Mar:300(1):203-219. PMID: 33586207

Kelly HG, Tan HX, Juno JA, Esterbauer R, Ju Y, Jiang W, Wimmer VC, Duckworth BC, Groom JR, Caruso F, Kanekiyo M, Kent SJ, Wheatley AK. Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation. JCI Insight 2020 May 21:5(10)e:136653. PMID: 32434990

Marsman C, Lafouresse F, Liao Y, Baldwin TM, Mielke LA, Hu Y, Mack M, Hertzog PJ, de Graaf CA, Shi W, Groom JR. Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation. Immunol Cell Biol. 2018 Nov;96(10):1083-1094. PMID: 29870118.

Groom JR, Richmond J, Murooka TT, Sorensen EW, Sung JH, Bankert K, von Andrian UH, Moon JJ, Mempel TR, Luster AD. CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4+ T helper 1 cell differentiation. Immunity. 2012 Dec 14;37(6):1091-103. PMID: 23123063.

T follicular helper (TFH) cells are a subset of effector CD4+ T cells that promote B cell maturation into high affinity plasma and memory cells. Almost all current vaccines protect via the induction of long-term antibody responses and circulating TFH numbers are reliable biomarkers of vaccination. How diverse pathogen-specific signals direct appropriate protective B cell responses is currently unknown.

This project combines diverse infection models, advanced imaging and transcriptional profiling to provide mechanistic insight into the processes underlying TFH heterogeneity, which is likely to be a key source of flexibility for adaptive immunity.

Further, a key outcome of this project is to identify mechanisms of TFH heterogeneity in order to treat antibody-dependent inflammatory diseases such as severe asthma, rheumatoid arthritis and lupus.

Project resources:
Sheikh AA, Groom JR. Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment. Cell Mol Immunol 2021 Mar;18(3):528-538. PMID: 32999454

Kealy L, Di Pietro A, Hailes L, Scheer S, Dalit L, Groom JR, Zaph C, Good-Jacobson KL. The Histone Methyltransferase DOT1L Is Essential for Humoral Immune Responses. Cell Rep 2020 Dec 15;33(11):108504. PMID: 33326791

Sheikh AA, Cooper L, Feng M, Souza-Fonseca-Guimaraes F, Lafouresse F, Duckworth BC, Huntington ND, Moon JJ, Pellegrini M, Nutt SL, Belz GT, Good-Jacobson KL, Groom JR. Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection. Cell Rep. 2019 Aug 13;28(7):1758-1772. PMID: 31412245

Piovesan D, Tempany J, Di Pietro A, Baas I, Yiannis C, O’Donnell K, Chen Y, Peperzak V, Belz GT, Mackay CR, Smyth GK, Groom JR, Tarlinton DM, Good-Jacobson KL. c-Myb Regulates the T-Bet-Dependent Differentiation Program in B cells to Coordinate Antibody Responses. Cell Rep. 2017 Apr 18;19(3):461-470. PMID: 28423310

Our immune system consists of specialised cells that collaborate to defeat invading pathogens. The integration of migration signals helps balance protective and memory differentiation fates, leading to clearance of infection and cancer and the establishment of immunological memory. How cells navigate these interactions is a dilemma of critical importance to human health globally.

This study uses advanced live imaging platforms to determine how T cells integrate complex migration cues. Further, we investigate the cell-type specific patrolling cues that control migration to inflammatory sites to clear infection and cancer.

Project resource:
Groom JR. Regulators of T-cell fate: Integration of cell migration, differentiation and function. Immunol Rev. 2019 May;289(1):101-114. PMID: 30977199

Following viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and promote protection, while simultaneously balancing the risk of severe immune pathology. The balance between immune protection and pathology has been highlighted in the coronavirus disease 2019 (COVID-19) pandemic.

COVID-19 patients can display a spectrum of symptoms that vary from mild, to severe and fatal immune pathology. How this pathophysiology range impacts the formation of protective, humoral immunity has not been tested.

Using our 3D imaging platforms we have identified new cellular networks that underpin the decision between inflammation or protection during viral infections. We will examine these T cell interactions in the context of different viral infections, including SARS-CoV-2 to identify therapies that reduce severe immune pathology and improve vaccination success.

Project resources:
Sheikh AA, Groom JR. Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment. Cell Mol Immunol 2021 Mar;18(3):528-538. PMID: 32999454

Sheikh AA, Cooper L, Feng M, Souza-Fonseca-Guimaraes F, Lafouresse F, Duckworth BC, Huntington ND, Moon JJ, Pellegrini M, Nutt SL, Belz GT, Good-Jacobson KL, Groom JR. Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection. Cell Rep. 2019 Aug 13;28(7):1758-1772. PMID: 31412245.