TCR and IL-7 Signaling Are Altered in the Absence of Functional GTPase of the Immune Associated Nucleotide Binding Protein 5 (GIMAP5)

Xi-Lin Chen,Subburaj Ilangumaran,Farnaz Ghobadi,Marian Mayhue,Sheela Ramanathan,Daniel Serrano,Kasper Hoebe,Antonio A Freitas

doi:10.1371/journal.pone.0151837

Abstract

GTPase of the immune associated nucleotide binding protein (GIMAP) family of proteins are expressed essentially in cells of the hematopoietic system. Mutation in the founding member of this gene family, Gimap5, results in the lymphopenic phenotype in Bio-Breeding diabetes prone rats. In mice, deletion of functional Gimap5 gene affects the survival and renewal of hematopoietic stem cells in addition to the defects observed in T cells. Here we show that T cells from OTII TCR-transgenic Gimap5sph/sph mice do not proliferate in response to its cognate antigen. Furthermore, T cells from Gimap5 mutant rats and mice show decreased phosphorylation of STAT5 following stimulation with IL-7. Our results suggest that functional Gimap5 is required for optimal signaling through TCR and IL-7R in T cells.

Highlights

Even though the GIMAP family of proteins was identified 15 years ago, very little is know about the mechanism of their action [1,2,3]
The total numbers of thymocytes are comparable with control rats even though the numbers of T cells show a profound reduction in the secondary lymphoid organs of Gimap5lyp/lyp rats [6]
The effect of mutations in Gimap5 begins to be manifested from SP stage of T cell development, even though Gimap5 expression is detected in double positive (DP) thymocytes [17]

Summary

Introduction

Even though the GIMAP family of proteins was identified 15 years ago, very little is know about the mechanism of their action [1,2,3]. In diabetes prone Bio Breeding rats, the lyp allele arises from a frame-shift mutation within the GTPase domain of the immune associated nucleotide binding protein 5 (Gimap5) gene [4, 5]. Among the proteins of the GIMAP family, Gimap has been studied in detail, as the gene is responsible for the lymphopenic phenotype in the diabetes prone Bio Breeding rats [6]. The domains in GIMAP5 do not show specific homology to any known protein family despite possessing an N-terminal GTPase domain and a Cterminal membrane anchor that localizes the protein to the lysosomes [7]. Gimap5lyp/lyp rats exhibit a profound T lymphopenia in the secondary lymphoid organs. In rats the lyp mutation shortens the lifespan of T cells in the secondary lymphoid organs [8]

Methods

Results

Conclusion