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Dr Marcin Pekalski

Research Interests

I am a life science researcher studying the development and aging of the immune system which is programmed at the metabolic, molecular and cellular level to maintain the multicellular body of human organism (of self-conscious organism that is also a habitat for microbes and forms the thermodynamic entity susceptible to changes in the outside environment including circadian and seasonal fluctuations).

I am working in the Diabetes and inflammation Laboratory (DIL) of John Todd and Linda Wicker where we work closely with statisticians and clinical scientists. I have established a collaboration with Dr Joanne Jones (Cambridge Neuroscience) important for studying the connection between nervous and immune system (neuroimmunology). We are investigating mechanisms of auto-immune and/or inflammation associated pathologies. We achieve this by combination of molecular, metabolic and immunological approaches including genome-wide /single cell methods i.e. RNA-sequencing at the single cell-level, FACS or mass cytometry, at the non-clinical and clinical level.  

I am particularly interested in mechanisms that orchestrate T cell homeostasis post their emigration from the thymus. Especially what controls the most unexperienced T cells - recent thymic emigrants (RTE) immigration/maturation to/within the peripheral compartments and is either followed by homeostatic expansion of naïve T cells or leads to naïve T cell activation towards specialized effector/ memory subsets (also associated with clinical pathologies). To what extent does the early-life education of the immune system (when the majority of naïve T cells are born in the thymus) impact its function later?

Recently we have demonstrated a link between the innate and adaptive immune system: Aging decreases thymic function in humans with naïve T cells being maintained by peripheral division, a process that remains poorly understood. Transcriptome profiling of naïve T cells revealed that complement receptors and molecules mediating microbial recognition and defense (i.e. IL8) are hallmarks of T cells as they leave the thymus. Furthermore, RTEs in humans are likely precursors of a novel antimicrobial, tissue homing Th8 lineage of lymphocytes. 

Keywords

Autoimmunity ; Multiple Sclerosis (MS) ; T cell differentiation ; Innate Immune System ; Recent Thymic Emigrants (RTE) ; Naïve T cells ; Homeostatic Expansion ; CD4+ ; Type 1 Diabetes (T1D) ; differentiation ; Neuro-immunology ; Complement System ; regulatory T cells ; Immune-ageing

Key Publications

Pekalski ML, Rubio Garcia A, Ferreira R, Rainbow D, Smyth D, Mashar M, Brady J, Savinykh N, XCastro Dopico X, Mahmood S, Duley S, Stevens H, Walker N, Cutler A, Waldron-Lynch F, Dunger D, Shannon-Lowe C, Coles A,  Jones J, Wallace C, Todd JA, Wicker LS,

Recent thymic emigrants produce antimicrobial IL-8, express complement receptors and are precursors of a tissue-homing Th8 lineage of memory cells

bioRxiv 059535; doi: http://dx.doi.org/10.1101/059535 (pre-print)

 

Todd JA, Pekalski ML, Cutler AJ, Evangelou M, Walker NM, Stevens HE et al

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

PLoS Med. 2016 Oct 11;13(10):e1002139.

 

Pekalski ML, Ferreira RC, Coulson RM, Cutler AJ, Guo H, Smyth DJ, Downes K, Dendrou CA, Castro Dopico X, Esposito L, Coleman G, Stevens HE, Nutland S, Walker NM, Guy C, Dunger DB, Wallace C, Tree TI, Todd JA, Wicker LS.

Postthymic expansion in human CD4 naive T cells defined by expression of functional high-affinity IL-2 receptors.

J Immunol. 2013 Mar 15;190(6):2554-66.

 

Dopico XC, Evangelou M, Ferreira RC, Guo H, Pekalski ML, Smyth DJ, Cooper N, Burren OS, Fulford AJ, Hennig BJ, Prentice AM, Ziegler AG, Bonifacio E, Wallace C, Todd JA.

Widespread seasonal gene expression reveals annual differences in human immunity and physiology.

Nat Commun. 2015 May 12;6:7000.

 

Ferreira RC, Simons HZ, Thompson WS, Cutler AJ, Dopico XC, Smyth DJ, Mashar M, Schuilenburg H, Walker NM, Dunger DB, Wallace C, Todd JA, Wicker LS, Pekalski ML.

IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients.

Diabetologia. 2015 Apr;58(4):781-90.

 

Ferreira RC, Freitag DF, Cutler AJ, Howson JM, Rainbow DB, Smyth DJ, Kaptoge S, Clarke P, Boreham C, Coulson RM, Pekalski ML, Chen WM, Onengut-Gumuscu S, Rich SS, Butterworth AS, Malarstig A, Danesh J, Todd JA.

Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.

PLoS Genet. 2013 Apr;9(4):e1003444.

 

Wallace C, Cutler AJ, Pontikos N, Pekalski ML, Burren OS, Cooper JD, García AR, Ferreira RC, Guo H, Walker NM, Smyth DJ, Rich SS, Onengut-Gumuscu S, Sawcer SJ, Ban M, Richardson S, Todd JA, Wicker LS.

Dissection of a Complex Disease Susceptibility Region Using a Bayesian Stochastic Search Approach to Fine

Mapping.

PLoS Genet. 2015 Jun 24;11(6):e1005272

 

Truman LA, Pekalski ML, Kareclas P, Evangelou M, Walker NM, Howlett J, Mander AP, Kennet J, Wicker LS, Bond S, Todd JA, Waldron-Lynch F.

Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes

(DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study.

BMJ Open. 2015 Dec 8;5(12):e009799.

 

Rainbow DB, Yang X, Burren O, Pekalski ML, Smyth DJ, Klarqvist MD, Penkett CJ, Brugger K, Martin H, Todd JA, Wallace C, Wicker LS.

Epigenetic analysis of regulatory T cells using multiplex bisulfite sequencing.

Eur J Immunol. 2015 Nov;45(11):3200-3.

 

Gammage PA, Gaude E, Van Haute L, Rebelo-Guiomar P, Jackson CB, Rorbach J, Pekalski ML, Robinson AJ, Charpentier M, Concordet JP, Frezza C, Minczuk M.

Near-complete elimination of mutant mtDNA by iterative or dynamic dose-controlled treatment with mtZFNs.

Nucleic Acids Res. 2016 Sep 19;44(16):7804-16.

 

Finak G, Langweiler M, Jaimes M, Malek M, Taghiyar J, Korin Y, Raddassi K, Devine L, Obermoser G, Pekalski ML, Pontikos N, Diaz A, Heck S, Villanova F, Terrazzini N, Kern F, Qian Y, Stanton R, Wang K, Brandes A, Ramey J, Aghaeepour N, Mosmann T, Scheuermann RH, Reed E, Palucka K, Pascual V, Blomberg BB, Nestle F, Nussenblatt RB, Brinkman RR, Gottardo R, Maecker H, McCoy JP.

Standardizing Flow Cytometry Immunophenotyping Analysis from the Human ImmunoPhenotyping Consortium.

Sci Rep. 2016 Feb 10;6:20686.

 

Bell CJ, Sun Y, Nowak UM, Clark J, Howlett S, Pekalski ML, Yang X, Ast O, Waldhauer I, Freimoser-Grundschober A, Moessner E, Umana P, Klein C, Hosse RJ, Wicker LS, Peterson LB.

Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

J Autoimmun. 2015 Jan;56:66-80.

 

Esposito L, Hunter KM, Clark J, Rainbow DB, Stevens H, Denesha J, Duley S, Dawson S, Coleman G, Nutland S, Bell GL, Moran C, Pekalski M, Todd JA, Wicker LS.

Investigation of soluble and transmembrane CTLA-4 isoforms in serum and microvesicles.

J Immunol. 2014 Jul 15;193(2):889-900

 

Thompson WS, Pekalski ML, Simons HZ, Smyth DJ, Castro-Dopico X, Guo H, Guy C, Dunger DB, Arif S, Peakman M, Wallace C, Wicker LS, Todd JA, Ferreira RC.

Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes.

Clin Exp Immunol. 2014 Sep;177(3):571-85.

 

Ferreira RC, Guo H, Coulson RM, Smyth DJ, Pekalski ML, Burren OS, Cutler AJ, Doecke JD, Flint S, McKinney EF, Lyons PA, Smith KG, Achenbach P, Beyerlein A, Dunger DB, Clayton DG, Wicker LS, Todd JA, Bonifacio E, Wallace C, Ziegler AG. A

type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes.

Diabetes. 2014 Jul;63(7):2538-50.

 

Downes K, Pekalski M, Angus KL, Hardy M, Nutland S, Smyth DJ, Walker NM, Wallace C, Todd JA.

Reduced expression of IFIH1 is protective for type 1 diabetes.

PLoS One. 2010 Sep 9;5(9). pii: e12646.

 

Pekalski M, Jenkinson SE, Willet JD, Poyner EF, Alhamidi AH, Robertson H, Ali S, Kirby JA.

Renal allograft rejection: examination of delayed differentiation of Treg and Th17 effector T cells.

Immunobiology. 2013 Mar;218(3):303-10.

 

Garg G, Tyler JR, Yang JH, Cutler AJ, Downes K, Pekalski ML, Bell GL, Nutland S, Peakman M, Todd JA, Wicker LS, Tree TI.

Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+

regulatory T cell function.

J Immunol. 2012 May 1;188(9):4644-53

 

Rorbach J, Richter R, Wessels HJ, Wydro M, Pekalski M, Farhoud M, Kühl I, Gaisne M, Bonnefoy N, Smeitink JA, Lightowlers RN, Chrzanowska-Lightowlers ZM.

The human mitochondrial ribosome recycling factor is essential for cell viability.

Nucleic Acids Res. 2008 Oct;36(18):5787-99.

 

Al-Hamidi A, Pekalski M, Robertson H, Ali S, Kirby JA.

Renal allograft rejection: the contribution of chemokines to the adhesion and retention of alphaE(CD103)beta7 integrin-expressing intratubular T cells.

Mol Immunol. 2008 Sep;45(15):4000-7

 

Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, Jones DE, Burt AD, Kirby JA.

Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease.

Lab Invest. 2008 Feb;88(2):112-23. PubMed PMID: 18059363.

 

Fernando A, Glaysher S, Conroy M, Pekalski M, Smith J, Knight LA, Di Nicolantonio F, Cree IA.

Effect of culture conditions on the chemosensitivity of ovarian cancer cell lines.

Anticancer Drugs. 2006 Sep;17(8):913-9. PubMed PMID:16940801.