Transgelin‐2 in immunity: Its implication in cell therapy

Transgelin‐2 is a small 22‐kDa actin‐binding protein implicated in actin dynamics, which stabilizes actin structures and participates in actin‐associated signaling pathways. Much curiosity regarding transgelin‐2 has centered around its dysregulation in tumor development and associated diseases. However, recent studies have shed new light on the functions of transgelin‐2, the only transgelin family member present in leukocytes, in the context of various immune responses. In this review, we outlined the biochemical properties of transgelin‐2 and its physiological functions in T cells, B cells, and macrophages. Transgelin‐2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse. Transgelin‐2 in B cells also participates in the stabilization of T cell–B cell conjugates. While transgelin‐2 is expressed at trace levels in macrophages, its expression is highly upregulated upon lipopolysaccharide stimulation and plays an essential role in macrophage phagocytosis. Since transgelin‐2 increases T cell adhesion to target cells via boosting the "inside‐out" costimulatory activation of leukocyte function‐associated antigen 1, transgelin‐2 could be a suitable candidate to potentiate the antitumor response of cytotoxic T cells by compensating for the lack of costimulation in tumor microenvironment. We discussed the feasibility of using native or engineered transgelin‐2 as a synergistic molecule in cell‐based immunotherapies, without inducing off‐target disturbance in actin dynamics in other cells.


INTRODUCTION
The actin cytoskeleton plays a crucial role for immune functions, orchestrating numerous cellular processes including cell proliferation and differentiation, apoptosis, migration, and cellular signaling. [1][2][3][4][5][6][7][8] To accomplish these outcomes, the actin filaments are spatially and temporally regulated by actin-binding proteins (ABPs), which account for approximately 25% of the total cellular protein. 9 Transgelin-2, a 22-kDa ABP, is encoded by the gene TAGLN2 and belongs to the transgelin superfamily of actin cross-linking/gelling proteins 10 consisting of transgelin-1 (also known as smooth muscle protein 22 , SM22 ), transgelin-2 (SM22 ), 11 and transgelin-3 (NP25). 12 Because the first member of the transgelin family, transgelin-1, was first identified in 1987 13 and has been considered as a tumor suppressor, 14  development and allied diseases. However, its fundamental mechanisms and physiological significance are largely unknown. Notably, recent findings regarding transgelin-2, the only transgelin family member present in leukocytes, 15 shed light on its biochemical properties and physiological roles in the immune system. In this review, we build a holistic picture of how transgelin-2 functions in cells of both innate and adaptive immune systems. We first provide the biochemical characteristics of transgelin-2 and its regulation in immune tissues and cells. We then review recently uncovered physiological functions of transgelin-2 in the immune system; this small ABP regulates cytoskele- The transgelin family has been assumed to consist of actin-bundling and gelling proteins. 24  this multimeric feature may suggest that it acts as a "molecular zipper or staple" for joining actin filaments into the bundles. The association of the N-terminus near the CH domain and the C-terminus CR region has been predicted as the mechanism of multimeric interactions of transgelin-2 at the site of actin polymerization. 15 The property of transgelin-2 allowing it to be intercalated into the each G-actin can also influence the stability of F-actins. 15

Expression and localization in various cell types
Transgelin-2 has been reported to be widely expressed in various cell types, from smooth muscle cells (SMCs) to non-SMCs, whereas the expressions of transgelin-1 and transgelin-3 are rather restricted to SMC and the brain, respectively. 29,30 However, of interest is that transgelin-2 is the only transgelin member expressed in immune tissues and cells, such as the thymus, spleen, lymph nodes, and primary immune cells and their cell lines. 15 In T cells, transgelin-2 expression is constitutive, although its expression is slightly altered by external stimulation. 15 In both bone marrow-derived and peritoneal macrophages, transgelin-2 is basally expressed in the resting state, but its expression is highly upregulated upon TLR-mediated macrophage activation. 17 In B cells, it is likely that the basal expression level is initially high and further elevated upon the activation of B cells, 31 although it remains contentious, 19 shown to be expressed in the nucleus as well, 15 whereas its functions within the nucleus have yet to be studied.

Regulation of transgelin-2 in immune cells
The regulation of transgelin-2 expression has not been sufficiently studied. However, some studies have suggested that transgelin-2 expression is controlled at the transcriptional, translational, and posttranslational levels in response to the various intercellular events.
For instance, transgelin-2 expression is linked to the NF-B pathway in macrophages. 17 45 This inverse correlation between these miRNAs, and transgelin-2 has been revealed in many cell carcinomas and normal cells, 44 has been shown to induce phosphorylation at S84 and S163, and mediates actin depolymerization, thus promoting cell invasion. 50 Furthermore, phosphorylation at S163 may be related to glucose-stimulated insulin secretion. 51

T Lymphocytes
In adaptive immunity, activated T lymphocytes play crucial roles by secreting cytokines or directly killing pathogen-infected cells or cancerous cells. For the full activation, spatial and temporal regulation of actin dynamics is crucial at the IS between T cells and APC. 6,52 Transgelin-2 is essential for T cell effector functions; it stabilizes cor- The activation of LFA-1, a leukocyte 2 integrin, and LFA-1/ICAM-1 interaction is the essential "outside-in" costimulatory signal for prolonged adhesion of T cells to APCs and thus T-cell activation. 15

B Lymphocytes
In B lymphocytes, transgelin-2 appears to be less crucial with respect to B-cell activation compared to its essential role in T-cell activation. In

Macrophages
Macrophages serve several essential roles at the initial host defense; they produce inflammatory cytokines and destroy pathogens by phagocytosis, which blocks early dissemination of pathogens. 62  in macrophages. 17 As a consequence, TAGLN2 knockout mice showed highly increased susceptibility to bacterial infection. 17

CONCLUDING REMARKS
The mechanisms underlying actin dynamics in a variety of immunological processes are quite sophisticated, involving the ABPs and interlaced signaling pathways. Transgelin-2 is actively involved in the actin cytoskeletal rearrangements and its expression seems to be up-or downregulated in different conditions, including BCR/TCR/TLR stimulation. Although transgelin-2 has been mainly studied within T cells, B cells, and macrophages, there have been other immune cell types that have been reported to express transgelin-2, such as dendritic cells (DCs). A proteomic analysis of differentially matured DCs demonstrated that transgelin-2 expression was highly upregulated in some DC subpopulations. 68 Moreover, it may be also worth mentioning that the DC cytoskeleton promotes T-cell adhesion and activation via ICAM-1 avidity alteration. 69 In this regard, the function of transgelin-2 in controlling the actin cytoskeleton in B cells, another APC, implies an important role of transgelin-2 in DCs as well. 19 Currently, our group is in the process of investigating how transgelin-2 functions in DCs.

DISCLOSURE
The authors declare no competing financial interests.