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oai:repisalud.isciii.es:20.500.12105/72362024-09-27T09:44:54Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Toribio-Fernandez, Raquel author 2019-01-18 A-type lamins (lamin A/C) are intermediate filament proteins that conform with B-type lamins the nuclear lamina (NL). The NL is localized just below the inner part of the nuclear envelope. Thus, the NL interacts with chromatin and transcription factors, modulating epigenetics and gene expression, among other essential functions as cell migration, proliferation, differentiation, and cell cycle progression. However, the most well-known function of lamin A/C is the maintenance of nuclear structure. Little information is known about the expression and function of A-type lamins in immune cells, and specifically in CD4+ T lymphocytes. CD4+ T-lymphocytes are one of the main components of the adaptive immunity, a very complex and a highly specialized immune response that defends the organism against infections. These lymphocytes need to interact through their T-cell receptor (TCR) with an antigen-presenting cell to become active, forming what is called immune synapse (IS). Once the TCR recognizes an antigen, lamin A/C has been shown to be expressed in the CD4+ T-cell, enhancing a proper IS formation and thus CD4+ T-cell activation. Due to its important role in T-cell activation, we hypothesized that lamin A/C might have also a role in proliferation, differentiation and effector function of CD4+ T lymphocytes. We have corroborated that lamin A/C significantly enhances T-cell activation in vivo, but it does not regulate T-cell proliferation. Interestingly, our results indicate that lamin A/C significantly determines the T-helper (Th) phenotype commitment. Hence, we have observed in vitro and in vivo that lamin A/C enhances Th1 differentiation, without affecting Th2 and Th17 phenotypes. Moreover, lamin A/C improves Th1 cells effector function against vaccinia virus (VACV) and Leishmania major infections in mice by enhancing CD4+ T cell cytotoxic capacity and Th1 effector response. Furthermore, Lmna-/- CD4+ T-cells protect from inflammatory bowel disease (IBD) development in mice enhancing regulatory T-cells (Treg) differentiation, and improving their suppressive function. The molecular mechanism by which lamin A/C determines Th fate is the upregulation of the Th1 master regulator (T-bet), and the downregulation of Treg master regulator (Foxp3). In more detail, lamin A/C epigenetically modifies the T-bet promoter enhancing its gene transcription. However, lamin A/C does not induce epigenetic changes in Foxp3 promoter. Besides, it is known that retinoic acid (RA) can regulate lamin A/C expression in leukocytes. Additionally, it has been described that CD103+ dendritic cells (DCs), mainly located in the mesenteric lymph nodes, release RA. We have demonstrated in mesenteric lymph nodes that the RA released by CD103+ DCs downregulates lamin A/C in CD4+ T-cells upon antigen recognition, enhancing Treg differentiation. In contrast, in spleen and peripheral lymph nodes, CD103- DCs are predominant and do not produce RA, facilitating lamin A/C expression in CD4+ T-cells upon antigen recognition, and thus, Th1 differentiation. By this physiological mechanism, lamin A/C levels can be modulated in different anatomical sites, in accordance with immunological requirements to control naïve T cell differentiation. Altogether, our findings set A-type lamins as key regulators of Th differentiation, and thus potential therapeutic targets for IBD and infectious diseases. 10.4321/repisalud.7236 http://hdl.handle.net/20.500.12105/7236 lamin A/C T-cell immune response Th1 Biological and pathological role of A-type lamins in T-cell mediated immune response