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Dr Michelle Linterman

Research Interests

The germinal center response is essential for production high affinity antibodies and the generation of immunological memory. Modification of the B cell receptor with microenvironment can also lead to production of centrocytes with self-reactive specificities, these are usually censored within the germinal center. The focus of my research is evaluating the contribution of breaks in germinal center tolerance to autoimmune disease.

In addition, Foxp3+ regulatory T cells (Tregs) are essential for maintaining immunological tolerance in both the homeostatic state and during an immune response to foreign antigen. Tregs modulate a diverse range of immune responses and thus they need to alter their migratory patterns and functional properties to be in the right place at the right time.  We have previously described the presence of Foxp3+ regulatory T cells in the germinal centre after immunisation, referred to as follicular regulatory T cells (Tfr).  We propose that Tfr are a subset of Tregs that specifically develop after immunisation to enter the germinal centre and modulate the response.

Keywords

FOXP3 ; B cells ; Fc receptors ; isotype switching ; T cells ; affinity maturation ; receptors ; somatic hypermutation

Topics

  • autoimmunity

Key Publications

Wallin EF, Jolly EC, Suchánek O, Bradley JA, Espéli M, Jayne DR, Linterman MA, Smith KG. Human T follicular helper and T follicular regulatory cell maintenance is independent of germinal centers. Blood. 2014 Sep 15. pii: blood-2014-07-585976. 

Denton AE, Roberts EW, Linterman MA, Fearon DT. Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells.
Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12139-44. 

Linterman MA. How T follicular helper cells and the germinal centre response change with age. Immunol Cell Biol. 2014 Jan;92(1):72-9.

Lee JC, Espéli M, Anderson CA, Linterman MA, Pocock JM, Williams NJ, Roberts R, Viatte S, Fu B,   Peshu N, Tran TH, Nguyen HP, Wesley E, Edwards C, Ahmad T, Mansfield JC, Gearry R, Dunstan S,   Williams TS, Barton A, Vinuesa CG, UK IBD Genetics Consortium, Parkes M, Lyons PA, Smith KGC.  Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.  Cell 2013: 155(1):57-69. 

Linterman MA, Liston A, Vinuesa CG. T-follicular helper cell differentiation and the co-option of this pathway by non-helper cells. Immunol Rev. 2012 May;247(1):143-59.

Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O, Kyewski B, Zuklys S, Hollander GA, Matthys P, Gray DH, De Strooper B, Liston A. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor. Nat Immunol. 2011 Dec 18;13(2):181-7.

Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KGC*, Vinuesa CG*. (*Joint senior authors) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011 Jul 24;17(8):975–82.

Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, Verma NK, Smyth MJ, Rigby RJ, Vinuesa CG. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 2010 Feb 8,

Linterman MA, Rigby RJ, Wong RK, Yu D, Brink R, Cannons JL, Schwartzberg PL, Cook MC, Walters GD, Vinuesa CG (Follicular helper T cells are required for systemic autoimmunity. J Exp Med 2009, Mar (3):561–76

Linterman MA, Rigby RJ, Wong R, Silva D, Withers D, Anderson G, Verma NK, Brink R, Hutloff A, Goodnow CC, Vinuesa CG. Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes Cd28 and Icos. Immunity 2009, Feb(2):228–41.

Spleen section from immunised mice at day7 stained with  an anti-IgD(red) , anti Bcl6 (green) an anti CD4 (blue) and Foxp3 (white) .The B cell follicle is stained with an anti-IgD whereas the germinal centre B cells are positive for BCL6. The differentiating T follicular helper (Tfh) cells can be identified by CD4+ BCL6+ staining. 

 

Spleen section from immunised mice at day7 stained with  an anti-IgD(red) , anti Bcl6 (green) an anti CD4 (blue) and Foxp3 (white) . The germinal centre  is identified by  IgD staining around the B cell follicle which is surrounded by CD4 + Foxp3+ regulatory T cells (Tregs) .

 

Tile scan of spleen section from immunised mouse at day7 stained with  an anti-IgD(red) , anti-Bcl6 (green) ,an anti-CD4 (blue) and Foxp3 (white). Picture represents the germinal centre formation at various locations which is identified by positive IgD staining around the B cell follicle and surrounded by CD4 + Foxp3+ T cell zone.