Abstract
The regulatory role of most dual specific phosphatases during T cell activation remains unknown. Here, we have studied the expression and function of phosphatases of regenerating liver (PRLs: PRL-1, PRL-2, and PRL-3) during T cell activation, as well as, the dynamic delivery of PRL-1 to the Immunological Synapse (IS). We found that T cell activation downregulates the expression of PRL-2, resulting in an increased PRL-1/PRL-2 ratio. PRL-1 redistributed at the IS in two stages: Initially, it was transiently accumulated at scanning membranes enriched in CD3 and actin, and at later times, it was delivered at the contact site from pericentriolar, CD3ζ-containing, vesicles. Once at the established IS, PRL-1 distributed to LFA-1 and CD3ε sites. Remarkably, PRL-1 was found to regulate actin dynamics during IS assembly and the secretion of IL-2. Moreover, pharmacological inhibition of the catalytic activity of the three PRLs reduced the secretion of IL-2. These results provide evidence indicating a regulatory role of PRL-1 during IS assembly and highlight the involvement of PRLs in immune responses by mature T cells.
Highlights
Antigen-induced activation of T lymphocytes is mediated by the formation of the immunological synapse (IS), a dynamic supra-molecular structure organized at the interface of interacting T lymphocytes and antigen presenting cells (APCs) [1]
The reported strong expression of PTP4A1 and PTP4A2 in the T cell area of lymph nodes [17] prompted us to evaluate the expression of the genes coding for PRLs in peripheral blood CD4 T lymphocytes. mRNA levels of PTP4A1, PTP4A2, and PTP4A3 were similar to those of other genes coding for classical PRL-1 at the Immunological SynapsePhospho-tyrosine phosphatases (PTPs) that regulate T cell immune responses, such as TCPTP/PTPN2, SHP1/PTPN6, or HePTP/PTPN7 [8] (Figure 1A)
In order to gain insight about the function of these molecules during T cell activation, we studied the regulation of mRNA expression levels of PTP4A1, PTP4A2, and PTP4A3 in in vitro expanded Th1 cells re-stimulated with phorbol esters and Iomomycin (PI treatment)
Summary
Antigen-induced activation of T lymphocytes is mediated by the formation of the immunological synapse (IS), a dynamic supra-molecular structure organized at the interface of interacting T lymphocytes and antigen presenting cells (APCs) [1]. The intracellular signaling downstream the T-cell receptor (TCR) triggers actin rearrangements, as well as, microtubule organizing center (MTOC) and endosomal compartment polarization to the IS. This cytoskeleton and endosomal compartment dynamics is critical for IS organization, sustains intracellular signaling and mediates cytokine secretion [2,3,4,5]. The function of DSPs in T cell activation is mostly unknown, except for some enzymes that regulate the intracellular signaling by MAPK or phospholipids [8, 11, 12]. The delivery of DSPs to the IS and their regulatory role in the dynamics of the cytoskeleton and the endosomal compartment during T cell immune responses have been barely studied [13, 14]
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