The T cell antigen receptor (TCR)
Signaling through the TCR controls adaptive immune responses. Antigen binding to the TCRab subunits transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by controversially discussed mechanisms. Together with the group of Prof. Schamel back in 2008, we elucidated how the antigen-induced TCR clustering and the CD3 conformational change cooperate to induce the phosphorylation of the TCR. However, the molecular mechanism that exactly connects this conformational change with the phosphorylation of the TCR remained unknown. In the last years, we have been joining our efforts to elucidate this mechanism. Thus, we have recently demonstrated that the TCRs on the surface of T cells are in equilibrium between an open conformation, which is accessible for phosphorylation, and a closed conformation protected from phosphorylation. This equilibrium is regulated by the binding of cholesterol to the TCRb chain, which shifts the TCR to the inactive conformation precluding spontaneous activation of T cells. Further, we have shown that ligand binding stabilizes the open conformation resulting in the phosphorylation of the TCR. Importantly, the TCR lacks intrinsic tyrosine kinase activity and is phosphorylated by the Src family kinase protein Lck. Lateral organization and compartmentalization of the plasma membrane is critical for Lck localization and its function in phosphorylating the TCR. Caveolin-1 (Cav1) regulates plasma membrane lateral organization and the compartmentalization of the plasma membrane in several cell types. Although, Cav1 expression in T cells has been controversial during the last 20 years, recent reports inspired our group to investigate if the absence of Cav1 impacted the relative distribution of Lck and the TCR prior to and after stimulation. Using primary cells, we have recently demonstrated that Cav1-/- CD4+ T cells failed to efficiently bring the TCR and Lck in close proximity upon TCR-activation. This finding supports the idea that, in the absence of Cav1, the nanoscale organization of the plasma membrane, most likely including the formation or stability of the cholesterol-enriched microdomains is altered. This affects the proximity between the TCR and Lck and in turn, productive TCR phosphorylation and activation of downstream signaling pathways. In the absence of Cav1, the strength of TCR signaling is reduced, and triggered CD4+ T cells preferentially convert into regulatory T cells in vivo. Importantly, this preferential generation of regulatory T cells in the absence of Cav1 directly translates into increased protection from the massive alloantigen driven inflammation in a highly relevant medical scenario, namely during graft-versus-host disease.
This project was awarded with a grant from the Else Kröner-Fresenius-Stiftung (2013-2014).
- Beck-Garcia K, Swamy M, Beck-Garcia E, Dopfer EP, Schulze AK, Deibel F, Molnár E, Borroto A, Höfer T, Minguet S§ and Schamel WWA§. “Cholesterol binding to TCRb guards the resting state of the T cell receptor”. Immunity 2016 May 17;44(5):1091-101. §Co-senior authors.
- Schönle A, Hartl FA, Mentzel J, Rauch KS, Wohlfeil SA, Nöltner T, Hechinger AK, Melchinger W, Fehrenbach K, Guadamillas MC, Prestipino A, Follo M, Prinz G, Ruess AK, Pfeifer D, Pozo MA, Schmitt-Graeff A, Duyster J, Blazar BR, Schachtrup K, Minguet S§ and Zeiser R§. “Caveolin-1 regulates TCR signal strength and regulatory T cell differentiation into alloreactive T cells” Blood. 2016 Apr 14;127(15):1930-9. §Co-senior authors
- Minguet S, Swamy M, Alarcon B, Luescher IF, Schamel WW. Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity. 2007 (1): 43-54.