Life Sciences Research for Lifelong Health

Geoff Butcher

Research Summary

In a healthy individual it is critically important that the number of mature T and B lymphocytes is maintained at a steady level. This process is termed lymphocyte homeostasis. The generation of new lymphocytes from precursor cells in the bone marrow and thymus is balanced by the loss of mature cells from peripheral compartments of the body.

Sometimes numbers of lymphocytes can increase dramatically, for example during infections. Once the infection has been successfully defeated by an immune response, lymphocyte numbers return to a normal level. The importance of maintaining lymphocyte homeostasis is evident from several immune diseases associated with having too few or too many lymphocytes. The regulation of lymphocyte survival vs. programmed cell death (apoptosis) is therefore essential to the survival of the healthy organism.

We are studying a family of signalling molecules called GTPases of the Immunity Associated Protein family (GIMAPs), which may play a part in the maintenance of lymphocyte populations.

Latest Publications

Survival of mature T cells in the periphery is intrinsically dependent on GIMAP1 in mice.
Datta P, Webb LM, Avdo I, Pascall J, Butcher GW

An effective immune system depends upon the survival of mature T cells in the periphery. Members of the GIMAP family of GTPases have been proposed to regulate this homeostasis, supported by the paucity of peripheral T cells in rodents deficient for either GIMAP1 or GIMAP5. It is unclear whether this lack of T cells is a consequence of an ontological defect, causing the thymus to generate and export T cells incapable of surviving in the periphery, or whether (alternatively or additionally) mature T cells intrinsically require GIMAP1 for survival. Using the ER(T2) Cre(+) transgene, we conditionally deleted Gimap1 in C57BL/6 mice and demonstrate that GIMAP1 is intrinsically required for the survival of mature T cells in the periphery. We show that, in contrast to GIMAP5, this requirement is independent of the T cell's activation status. We investigated the nature of the survival defect in GIMAP1-deficient CD4(+) T cells and show that the death occurring after GIMAP1 ablation is accompanied by mitochondrial depolarisation and activation of the extrinsic apoptotic pathway. This study shows that GIMAP1 is critical for maintaining the peripheral T-cell pool in mice and offers a potent target for the treatment of T-cell-mediated diseases. This article is protected by copyright. All rights reserved.

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European journal of immunology, , 1521-4141, , 2016

PMID: 27792288

GIMAP1 Is Essential for the Survival of Naive and Activated B Cells In Vivo.
Webb LM, Datta P, Bell SE, Kitamura D, Turner M, Butcher GW

An effective immune system depends upon regulation of lymphocyte function and homeostasis. In recent years, members of the GTPases of the immunity associated protein (GIMAP) family were proposed to regulate T cell homeostasis. In contrast, little is known about their function and mode of action in B cells. We used a combination of transgenic mice and in vivo and in vitro techniques to conditionally and electively ablate GIMAP1 in resting and activated peripheral B cells. Our data suggest that GIMAP1 is absolutely essential for the survival of peripheral B cells, irrespective of their activation state. Together with recent data showing increased expression of GIMAP1 in B cell lymphomas, our work points to the possible potential of GIMAP1 as a target for manipulation in a variety of B cell-mediated diseases.

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Journal of immunology (Baltimore, Md. : 1950), , 1550-6606, , 2015

PMID: 26621859

Generation and characterisation of mice deficient in the multi-GTPase domain containing protein, GIMAP8.
Webb LM, Pascall JC, Hepburn L, Carter C, Turner M, Butcher GW

GTPases of the immunity-associated protein family (GIMAPs) are predominantly expressed in mature lymphocytes. Studies of rodents deficient in GIMAP1, GIMAP4, or GIMAP5 have demonstrated that these GTPases regulate lymphocyte survival. In contrast to the other family members, GIMAP8 contains three potential GTP-binding domains (G-domains), a highly unusual feature suggesting a novel function for this protein. To examine a role for GIMAP8 in lymphocyte biology we examined GIMAP8 expression during lymphocyte development. We also generated a mouse deficient in GIMAP8 and examined lymphocyte development and function.

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PloS one, 9, 1932-6203, e110294, 2014

PMID: 25329815

 

Group Members

Latest Publications

Survival of mature T cells in the periphery is intrinsically dependent on GIMAP1 in mice.

Datta P, Webb LM, Avdo I

European journal of immunology
1521-4141: (2016)

PMID: 27792288

GIMAP1 Is Essential for the Survival of Naive and Activated B Cells In Vivo.

Webb LM, Datta P, Bell SE

Journal of immunology (Baltimore, Md. : 1950)
1550-6606: (2015)

PMID: 26621859

Generation and characterisation of mice deficient in the multi-GTPase domain containing protein, GIMAP8.

Webb LM, Pascall JC, Hepburn L

PloS one
9 1932-6203:e110294 (2014)

PMID: 25329815

The miR-155-PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation.

Lu D, Nakagawa R, Lazzaro S

The Journal of experimental medicine
211 1540-9538:2183-98 (2014)

PMID: 25288398

Gimap3 and Gimap5 cooperate to maintain T-cell numbers in the mouse.

Yano K, Carter C, Yoshida N

European journal of immunology
44 1521-4141:561-72 (2014)

PMID: 24510501

The autoimmunity-related GIMAP5 GTPase is a lysosome-associated protein.

VW Wong, AE Saunders, A Hutchings

Self/nonself
1 3:259-268 (2010)

DOI: 10.4161/self.1.3.12819

PMID: 21487483