THEMIS: Two Models, Different Thresholds

Abstract

THEMIS, a recently identified T-lineage restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR); but the mechanistic underpinnings of THEMIS’ function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling. However, new data suggest an alternative model where THEMIS enhances TCR signaling, enabling thymocytes to reach the threshold for positive selection avoiding death by neglect. We review the data supporting each model and conclude that the preponderance of evidence favors an enhancing function for THEMIS in TCR signaling.

T cell self-reactivity during thymic development dictates the timing of positive selection

“…Interestingly, all eleven genes correlated with low self-reactivity, particularly at the early DP stage of development. This included Themis (Figure 6-figure supplement 2b), which encodes a protein required for modulating TCR signaling during positive selection (Lesourne et al 2009;Patrick et al 2009;Kakugawa et al 2009;Fu et al 2009;Johnson et al 2009;Choi, Warzecha, et al 2017;Choi, Cornall, et al 2017;Mehta et al 2018). Moreover, expression of the curated set of ion channel genes in the ImmGen microarray data set revealed that group 2 genes, whose expression correlated with low self-reactivity, also displayed higher expression in preselection wildtype thymocytes (Figure 6-figure supplement 2c).…”

“…A number of molecules have been identified which are involved in modulating TCR signaling in DP thymocytes, and which are downregulated during positive selection. These include the microRNA miR-181a: which enhances TCR signaling by downregulating a set of protein phosphatases (Li et al 2007), Tespa1: a protein that enhances calcium release from the ER (Lyu et al 2019;Liang et al 2017), components of a voltage gated sodium channel (VGSC): that prolongs calcium flux via an unknown mechanism (Lo, Donermeyer, and Allen 2012), and Themis: a TCR associated protein with controversial function (Kakugawa et al 2009;Patrick et al 2009;Lesourne et al 2009;Johnson et al 2009;Fu et al 2009;Choi, Cornall, et al 2017;Fu et al 2013;Choi, Warzecha, et al 2017;Mehta et al 2018). While a diverse set of potential players have been identified, a clear understanding of the mechanisms that render preselection DP thymocytes sensitive to low affinity self-ligands remains elusive.…”

MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

“…Modulation of SHP-1 activity has been proposed to be the key mechanism of action of Themis, a modulator of TCR signal strength predominantly expressed in DP thymocytes [ 19 , 20 ]. However, it remains controversial whether Themis inhibits or promotes SHP-1 activity [ 19 , 21 ]. Taken together, in thymocytes, the TCR converts signals elicited by pMHC ligands with a continuum of affinities to a digital outcome of positive selection or clonal deletion.…”

The RAG1 Ubiquitin Ligase Domain Enhances the Assembly and Selection of T Cell Receptor Genes to Restrain the Autoimmune Hazard of Generating T Cell Receptor Diversity

“…This differential is thought to enable positive selection from low affinity/avidity interactions, prevent the same contacts from activating mature ab T cells, and provide a "safety net" for negative selection to more effectively suppress autoimmunity (6)(7)(8)(9). Although the T lineage-specific Themis protein contributes to this differential in TCR sensitivity between immature and mature ab T cells (9,15,16), the precise mechanisms by which this protein and possibly additional factors "tune" TCR signaling and control ab TCR selection remain to be elucidated.…”