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

GIMAP6 is required for T cell maintenance and efficient autophagy in mice.
Pascall JC, Webb LMC, Eskelinen EL, Innocentin S, Attaf-Bouabdallah N, Butcher GW

The GTPases of the immunity-associated proteins (GIMAP) GTPases are a family of proteins expressed strongly in the adaptive immune system. We have previously reported that in human cells one member of this family, GIMAP6, interacts with the ATG8 family member GABARAPL2, and is recruited to autophagosomes upon starvation, suggesting a role for GIMAP6 in the autophagic process. To study this possibility and the function of GIMAP6 in the immune system, we have established a mouse line in which the Gimap6 gene can be inactivated by Cre-mediated recombination. In mice bred to carry the CD2Cre transgene such that the Gimap6 gene was deleted within the T and B cell lineages there was a 50-70% reduction in peripheral CD4+ and CD8+ T cells. Analysis of splenocyte-derived proteins from these mice indicated increased levels of MAP1LC3B, particularly the lipidated LC3-II form, and S405-phosphorylation of SQSTM1. Electron microscopic measurements of Gimap6-/- CD4+ T cells indicated an increased mitochondrial/cytoplasmic volume ratio and increased numbers of autophagosomes. These results are consistent with autophagic disruption in the cells. However, Gimap6-/- T cells were largely normal in character, could be effectively activated in vitro and supported T cell-dependent antibody production. Treatment in vitro of CD4+ splenocytes from GIMAP6fl/flERT2Cre mice with 4-hydroxytamoxifen resulted in the disappearance of GIMAP6 within five days. In parallel, increased phosphorylation of SQSTM1 and TBK1 was observed. These results indicate a requirement for GIMAP6 in the maintenance of a normal peripheral adaptive immune system and a significant role for the protein in normal autophagic processes. Moreover, as GIMAP6 is expressed in a cell-selective manner, this indicates the potential existence of a cell-restricted mode of autophagic regulation.

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PloS one, 13, 1932-6203, e0196504, 2018

PMID: 29718959

Multi-tissue DNA methylation age predictor in mouse.
Stubbs TM, Bonder MJ, Stark AK, Krueger F, Bolland D, Butcher G, Chandra T, Clark SJ, Corcoran A, Eckersley-Maslin M, Field L, Frising UC, Gilbert C, Guedes J, Hernando-Herraez I, Houseley J, Kemp F, MacQueen A, Okkenhaug K, Rhoades M, Santbergen MJC, Stebegg M, von Meyenn F, Stegle O, Reik W

DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse.

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Genome biology, 18, 1474-760X, 68, 2017

PMID: 28399939

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

Group Members

Latest Publications

GIMAP6 is required for T cell maintenance and efficient autophagy in mice.

Pascall JC, Webb LMC, Eskelinen EL

PloS one
13 1932-6203:e0196504 (2018)

PMID: 29718959

Multi-tissue DNA methylation age predictor in mouse.

Stubbs TM, Bonder MJ, Stark AK

Genome biology
18 1474-760X:68 (2017)

PMID: 28399939

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