SIT and TRIM Determine T Cell Fate in the Thymus

Abstract

Thymic selection is a tightly regulated developmental process essential for establishing central tolerance. The intensity of TCR-mediated signaling is a key factor for determining cell fate in the thymus. It is widely accepted that low-intensity signals result in positive selection, whereas high-intensity signals induce negative selection. Transmembrane adaptor proteins have been demonstrated to be important regulators of T cell activation. However, little is known about their role during T cell development. Herein, we show that SIT (SHP2 Src homology domain containing tyrosine phosphatase 2-interacting transmembrane adaptor protein) and TRIM (TCR-interacting molecule), two structurally related transmembrane adaptors, cooperatively regulate TCR signaling potential, thereby influencing the outcome of thymic selection. Indeed, loss of both SIT and TRIM resulted in the up-regulation of CD5, CD69, and TCRβ, strong MAPK activation, and, consequently, enhanced positive selection. Moreover, by crossing SIT/TRIM double-deficient mice onto transgenic mice bearing TCRs with different avidity/affinity, we found profound alterations in T cell development. Indeed, in female HY TCR transgenic mice, positive selection was completely converted into negative selection resulting in small thymi devoided of double-positive thymocytes. More strikingly, in a nonselecting background, SIT/TRIM double-deficient single-positive T cells developed, were functional, and populated the periphery. In summary, we demonstrated that SIT and TRIM regulate cell fate of developing thymocytes, thus identifying them as essential regulators of central tolerance.

microRNAs at the regulatory frontier: an investigation into how microRNAs impact the development and effector functions of CD4 T cells

“…More strikingly, this increase also allows miR-181a to effectively convert an antagonist to an agonist, eliciting TCR signaling. The mechanism involves the downregulation of a network of phosphatases responsible for negatively regulating distinct steps of TCR signaling: PTPN22, which removes activating phosphorylation on Lck and ZAP70 [30,31]; SHP2, an effector for inhibitory transmembrane adapter proteins (TRAPs) such as SIT and TRIM, which have also been shown to influence thymocyte sensitivity and tolerance [32]; DUSP5, which dephosphorylates activated ERK in the nucleus; and DUSP6, which targets cytosolic ERK1/2 [33]. Notably, miR-181a only moderately represses each target (a decrease in protein level as small as 40%), and the synergistic repression of multiple targets in the network is required.…”

Functional Development of the T Cell Receptor for Antigen

“…103 microRNAs are ~20–22 nucleotide RNAs in their mature form and exert their influence in combination with proteins of the RNA-induced silencing complex (RISC) by targeting mRNAs for degradation or translational repression. 104 We previously showed 105 that miR-181a suppresses multiple phosphatases that negatively regulate the TCR signaling cascade: Ptpn22, which targets the activating phosphorylation sites of lck and ZAP70 106,107 ; Shp2, an effector for inhibitory transmembrane adapter proteins (TRAPs) such as SIT and TRIM, which have also been shown to influence thymocyte sensitivity and tolerance 108 ; DUSP5, which dephosphorylates activated Erk in the nucleus; and DUSP6, which targets cytosolic Erk. 109 While each of these four targets was repressed only moderately, from two- to fivefold, overexpression of miR-181a in mature T cells resulted in a dramatic shift in their responsiveness, in the form of both higher absolute calcium signals, an ability to respond to fewer agonist pMHCs than are normally required, and the ability to respond to pMHC ligands that normally are too weak to stimulate a response.…”

Stoichiometry and intracellular fate of TRIM-containing TCR complexes

“…TRIM is phosphorylated upon TCR-stimulation by Src protein tyrosine kinases [16] and, together with other transmembrane adapter proteins (e.g. SIT), modulates TCR-mediated signals thereby regulating thymocyte development [22,23]. The precise signaling function of TRIM remains elusive, since the TRIM knock-out mouse did not show any phenotype in the assays employed [22].…”