Understanding the persistence of immunological memory

Project type

PhD

Supervisor(s)	Division	Email
Associate Professor David Tarlinton (Primary)	Immunology	.(JavaScript must be enabled to view this email address)
Professor Phil Hodgkin (Co-supervisor)	Immunology	.(JavaScript must be enabled to view this email address)

Details of project

Lymphocytes change their survival strategy during their differentiation into long-lived memory cells and antibody-secreting, plasma cells. Survival is at one level controlled by inhibiting apoptosis, a term describe a particular albeit common form of cell death. Apoptosis in turn is controlled by the balance between proteins acting to sustain cells (anti-apoptotic) and those intent on killing cells (pro-apoptotic). There are several proteins in both groups that are known to have different biochemical properties, raising questions of why they are used differentially. We have examined this in an immune response to foreign antigen and found that one protein, Mcl1, is critical for sustaining the B lymphocyte immune response (Figure 1) while other proteins, Bcl2 and BclxL, are important in sustaining early plasma cells.

The aim of this project is to examine the signals that control expression of these pro-survival proteins in B cells during an immune response. This is a particularly interesting question with regard to Mcl1, which is known to increase in antigen activated B cells. Very little is known about the regulation of the expression of this important protein during B lymphocyte activation and differentiation, but it is known from other systems to be subject to both transcriptional and post-translational regulation.

The project will investigate the control of transcription of the Mcl1 gene and turnover of the protein in the different stages of B cell differentiation. It aims to identify the environmental components and the signaling pathways that they activate in B cells to sustain Mcl1 expression. This work has implications for immunological memory, cancers of the immune system and autoimmune diseases.

<p>Figure 1: The B cell immune response requires Mcl1. Here we have used histology of the spleen of an immunised mouse to show the B cell areas (red) and within them, B cells undergoing an immune response (green). By deleting both alleles of Mcl1 specifically in the antigen-reactive B cells, using a specific form of Cre called AID-Cre, we showed that Mcl1 is essential for survival of activated B cells. Compare the right panel with both alleles of Mcl1 deleted to the controls. From Vikstrom et al., Science 2010.
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Project references

Vikstrom IB, Carotta S, Luethje K, Peperzak V, Josp PJ, Glaser S, Busslinger M, Bouillet P, Strasser A, Nutt SL, Tarlinton DM. Mcl-1 is essential for germinal center formation and memory. Science 2010 330:1095-1099
Carrington EM, Vikstrom IB, Light A, Sutherland RM, Londrigan SL, Mason KD, Huang DC, Lew AM, Tarlinton DM. BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc. Natl. Acad. Sci. USA. 2010 107: 10967-10971
Vikstrom IB, Tarlinton DM. B cell memory and the role of apoptosis in its formation. Mol. Immunol. 2011 48:1301-1306

Research interests

The Tarlinton laboratory is interested in the development of immune responses. This comprises beneficial immune responses to foreign antigens, symbolised most appropriately by vaccines, and destructive immune responses to self-antigens that characterise autoimmune diseases.

The laboratory examines the formation and persistence of immunological memory, examining the cellular and molecular characteristics that distinguish the development of long-lived memory lymphocytes and plasma cells (the cell responsible for antibody secretion). This encompasses the use of genetically manipulated mice to examine the role of individual factors in either the development of immunity or autoimmunity, as well as searching for factors that might allow manipulation of the immune response, be that increasing the magnitude or persistence of a vaccine response or attenuating a self-reactive response.

The laboratory uses a combination of cellular and molecular approaches to address questions of immunity. These include sophisticated, multi-parameter flow cytometry, analysis of the gene expression pattern in defined cell types and examination of cell movement in organs and in response to discrete stimuli.

Selected publications

Zotos D, Coquet JM, Zhang Y, Light A, D’Costa K, Kallies A, Corcoran LM, Godfry DI, Toellner KM, Smyth MJ, Nutt SL, Tarlinton DM. IL-21 Regulates Germinal Center B Cell Differentiation and Proliferation Through a B Cell-intrinsic Mechanism. J. Exp. Med. 2010 207:365-378
Oracki SA, Walker JA, Hibbs ML, Corcoran LM, Tarlinton DM. Plasma cell development and survival. Immunol. Rev. 2010 237:140-159
Nutt SL, Tarlinton DM. Germinal center B and follicular helper T cells: siblings, cousins or just good friends? Nat. Immunol. 2011 131:472-477

Research theme

Infectious diseases

Scientific discipline

Cell Biology
Immunology
Molecular Biology

Keywords

Apoptosis; Cell Signalling

The Walter and Eliza Hall Institute of Medical Research