Novel isoforms of the giant protein Titin in the regulation of lymphocyte trafficking

Titin (TTN) is the largest protein in the human genome and is mainly known as the third component of the sarcomere together with actin and myosin. In this context, TTN is responsible for maintaining muscle passive stiffness providing structural, scaffolding, and mechano-signaling properties. Here, we describe unexpected role of TTN in the regulation of human lymphocyte physiology. Human T lymphocytes express three novel TTN isoforms exhibiting cell-specific expression and different distribution to subcellular compartments. By performing fluorescence microscopy 3D imaging, we found that the LTTN1 and the LTTN2 isoforms span cytosolic as well as nuclear compartments, whereas the smallest LTTN3 isoform seems to be restricted to the cytosol. Recent data from our laboratory showed that LTTN1 covers a pivotal role in immune system physiology. Indeed, LTTN1 controls microvilli stricture and, thus, selectin-mediated tethering and rolling, chemokinetriggered integrin activation, chemotaxis, and in vitro cell deformability underflow. The new in vivo data confirmed LTTN1 putative role in T lymphocytes resilience to mechanical stress induced by passive deformation in the microcirculation. This makes LTTN1 a crucial player not only in multiple steps of T lymphocyte trafficking but, and importantly, in T lymphocyte survival. Besides LTTN1, we demonstrated that also LTTN3 is involved in the inside-out pathway of chemokinetriggered integrin activation. LTTN3 facilitates chemotaxis and controls chemokine-triggered integrin-mediated adhesion. Accordingly, it mediates RhoA and Rac1 small GTPases activation. Thus, while LTTN1 is a critical housekeeping regulator of T lymphocyte physiology, our results also suggest a possible involvement of LTTN3 as a central modulator of chemokine-induced signal transduction in T lymphocytes.