The Mitochondrial Protein TCAIM Regulates Activation of T Cells and Thereby Promotes Tolerance Induction of Allogeneic Transplants

Abstract

Primary T cell activation and effector cell differentiation is required for rejection of allogeneic grafts in na€ ıve recipients. It has become evident, that mitochondria play an important role for T cell activation. Expression of several mitochondrial proteins such as TCAIM (T cell activation inhibitor, mitochondrial) is down-regulated upon T cell receptor triggering. Here we report that TCAIM inhibited spontaneous development of memory and effector T cells. CD4 þ T cells from Tcaim knock-in (KI) mice showed reduced activation, cytokine secretion and proliferation in vitro. Tcaim KI T cells tolerated allogeneic skin grafts upon transfer into Rag-1 KO mice. CD4 þ and CD8 þ T cells from these mice did not infiltrate skin grafts and kept a na€ ıve or central memory phenotype, respectively. They were unable to acquire effector phenotype and functions. TCAIM altered T cell activation-induced mitochondrial distribution and reduced mitochondrial reactive oxygen species (mROS) production. Thus, TCAIM controls T cell activation and promotes tolerance induction probably by regulating TCR-mediated mitochondrial distribution and mROS production.

Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance

“…In a rat KTx model, intragraft expression of TCAIM was dramatically reduced in untreated rejecting recipients and in recipients who received an adoptive transfer of memory T cells [ 40 ]. Recently, it was shown that TCAIM inhibited spontaneous development of memory and effector T cells [ 41 ]. Higher FOXP3 and TCAIM expressions along with Treg numbers in basiliximab group may suggest a protective potential of basiliximab.…”

Super-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications

“…HIF1α also increases glycolysis by upregulating GLUT1, and promotes FOXP3 ubiquitination. LKB1 and TCAIM ( 67 ) promoting glycolysis are promising candidates for consideration. CD39 participates in tolerance induction in kidney grafts ( 68 ) and the effector memory Treg subset mainly expressing CD39 is diminished in multiple sclerosis ( 69 ).…”

TCAIM Decreases T Cell Priming Capacity of Dendritic Cells by Inhibiting TLR-Induced Ca2+ Influx and IL-2 Production

“…The 7500 Real-Time PCR system was used to detect gene expression for mouse tcaim or IL-2 (mIl2). The primer sequences used to quantify mouse tcaim expression have been published previously (19), whereas the primer sequences used to quantify mouse mIl2 are as follows: Il2 sense 59-TCGCCAGTCAAGAGCTTCA-GACAAGCA-39, anti-sense 59-CATGCCGCAGAGGTCCAA-39 (MWG Biotech AG). Primers applied for the detection of mHprt were reported previously (1).…”