it is composed by the outer and inner nuclear membranes , the nuclear pore complexes and the nuclear lamina . the outer nuclear membrane ( onm ) forms a continuum with the endoplasmic reticulum , whereas the inner nuclear membrane ( inm ) is aligned with the nuclear lamina . within the nucleus , the nuclear lamina is made of a meshwork of type v intermediate - filament proteins called lamins . it is tightly associated to several inm - associated proteins and interacts with portions of the chromatin . they are encoded by different genes : lmnb1 encodes lamin b1 , lmnb2 encodes lamin b2 and lamin b3 proteins , and lmna encodes the major forms lamin a and c , and also lamins a10 and c2 . a - type lamins provide mechanical stability to the nucleus and have been linked to the regulation of various cellular processes , including nuclear positioning , higher - order chromatin organization , nuclear pore complex organization , gene transcription , nuclear envelope breakdown and reassembly during mitosis , dna replication , dna damage response , cell cycle progression , cell differentiation , and cell polarization during migration . these functions have been addressed in a variety of cell types , but only a few have been performed in immune cells . in this review , we provide a brief overview of the role of lamins in lymphocytes with emphasis on our recent study demonstrating that lamin a is an important modulator of t cell activation . t cell activation occurs following the recognition of foreign antigens presented by antigen - presenting cells ( apcs ) . during this process , t cells and apcs form cell - cell contacts , called immunological synapses ( is ) . these specialized cell - cell contacts are characterized by a highly organized structure that enables efficient , transient cell - cell communication . is formation and maintenance involves the controlled recruitment of membrane receptors to specific subcellular sites , e.g. , an accumulation of the t - cell receptor ( tcr ) and cd3 at the central supramolecular activation cluster ( csmac ) ; and an accumulation of actin , integrins , and other adhesion molecules at the surrounding peripheral smac ( psmac ) . t cell activation also requires translocation of the microtubule - organizing center ( mtoc ) toward the t cell - apc contact . previous studies have reported the absence of lamin a / c in unstimulated human and mouse t lymphocytes . conversely , rober and collaborators have observed a few lamin a / c - positive lymphocytes from rat bone marrow cultures . lamin a / c expression has also been reported in activated human peripheral blood lymphocytes , cd4 t lymphocytes and in cd30 lymphoid cells . we have observed that although few resting human and mouse t lymphoblasts expressed lamin a , its presence was transiently and considerably increased upon t cell activation following cognate immune interactions . the amount of a - type lamins during the interphase of somatic cells is quite stable , exhibiting slow subunit exchange . however , we found a rapid production of lamin a / c mrna and protein upon t cell activation . this is consistent with the fact that mature lamin a can be formed 2 h after synthesis of the pre - lamin a precursor in other cell types . the specific signaling pathway mediating lamins a / c gene expression remains to be determined . akt / pkb pathway might play a role in this process , since it is induced during t cell activation , and it is involved in pre - lamin a transcription in interphase of other cell types , possibly through the regulation of the transcription factors foxo , sp1/sp3 , ap1 and creb . in our study , the peak of lamin a / c production in activated t cells was followed by a steep decrease . this decrease could be due to a reduced de novo synthesis and/or an increased degradation of lamin a / c proteins . an additional possibility is that expression in lymphoid cells is controlled by micrornas . in this regard , lamin a , but not lamin c , levels in the brain are regulated by the microrna mir-9 . in mice , lamin a / c absence induces severe age - dependent defects in t and b cell development , which have been associated with indirect effects related to the loss of a - type lamins in non - immune cells . however , we observed that splenocytes and cd4 t cells isolated from spleens of lmna mice exhibited decreased activation in response to different tcr - dependent stimuli ( fig .  1 ) , displaying reduced mrna and protein expression of the t - cell activation markers cd25 (  chain of the il-2 receptor , il-2r ) and cd69 . also , by using a hapten - induced contact hypersensitivity ( chs ) model , we demonstrated that lamin a / c proteins modulate the immune response in vivo . wild - type irradiated mice reconstituted with bone marrow cells from lmna mice exhibited reduced ear inflammation . moreover , adoptively transferred wild - type animals displayed reduced accumulation of lmna cd4 t cells in ears , lymph nodes , and spleens , suggesting that lamin a / c could regulate t cell proliferation and/or migration after antigen recognition . a - type lamins control key points of tcr - dependent increase of t - cell activation . tcr ligation results in the formation of signaling microclusters enriched in receptors and co - receptors , including the tcr and cd3 , kinases and adaptor proteins that generate signaling events . a - type lamins induce an increase in tcr / cd3 clustering at the csmac of the is , enhancing the phosphorylation of its downstream signaling targets . zap-70 ( -chain - associated protein of 70 kd ) associates with the tcr and phosphorylates , among other targets , lat ( linker of activated t cells ) and slp-76 ( sh2 domain - containing leukocyte protein of 76 kd ) . upon phosphorylation , lat recruits plc1 , which induces the mtoc polarization toward the is ( discontinued arrow ) . lamin a expression enhances plc1 phosphorylation , accelerating mtoc translocation to the cell - cell contact . upon phosphorylation by zap-70 , slp-76 binds to the guanine nucleotide exchange factor ( gef ) vav-1 , which favors actin filament formation . lamin a expression also stimulates vav1 phosphorylation , leading to an increase in f - actin polymerization . miia phosphorylation is also increased by the expression of a - type lamins , contributing to both tcr / cd3 dynamic clustering at the membrane and actin polymerization . polymerized actin modulates in turn the movement of tcr / cd3 microclusters and signaling proteins at the membrane . expression of a - type lamins enhances erk1/2 phosphorylation , which could be due to a tcr - dependent mechanism or to a direct interaction with lamin a / c . a - type lamins expression in t cells promotes the gene expression of t - cell activation molecules . it increases the membrane expression of the t - cell activation molecules cd69 and cd25 ( il-2r ) , which is dependent on erk1/2 phosphorylation . in the illustration , ectopic expression of lamin a in the lamin a - deficient human t cell line jurkat increased basal levels of t cell activation upon antigen recognition , enhancing cd25 and cd69 mrna and protein expression ( fig .  1 ) . these results suggest that lamin a modulates t cell activation by triggering changes in protein transcription . in this sense , a - type lamins can modulate gene expression through the interaction with signaling proteins , as erk1/2 ( extracellular signal - related kinase 1/2 ) , and transcription factors , as c - fos . erk1/2 activation modulates cd69 and cd25 expression , and lamin a expression in jurkat t cells enhances erk1/2 phosphorylation . moreover , erk1/2 inhibition prevents the lamin a - dependent increase in surface cd69 expression ( fig .  1 ) , further confirming that lamin a modulates t cell activation by regulating the transcription of t cell activation markers . lamin a expression in jurkat t cells also facilitates and stabilizes is formation , as measured by the quantification of the total number of conjugates and their cell - cell interaction time using confocal and time - lapse confocal microscopy . using confocal and tirf ( total internal reflection fluorescence ) microscopy to analyze the distribution and dynamics of tcr / cd3 complexes at the csmac of the is , we showed that lamin a ectopic expression in jurkat t cells enhances the dynamic redistribution and internalization of these complexes ( fig .  1 ) . it also increases the phosphorylation of cd3 downstream signaling molecules , as plc1 ( phospholipase c 1 ) , vav1 , myosin iia ( miia ) , and erk1/2 ( fig .  1 ) . these data suggest that the lamin a / c - induced increase in intracellular signaling was related to the regulation of the lymphocyte cytoskeleton . lamin a - expressing cells exhibited a more dynamic mtoc translocation toward the is , increased f - actin polymerization upon tcr stimulation , and enhanced f - actin accumulation at the is ( fig .  1 ) . accordingly , lamin a / c knock - down in activated primary t lymphoblasts resulted in reduced f - actin polymerization upon conjugation with apcs , further confirming that a - type lamins are required for f - actin polymerization during t cell activation . lamin a connects the nucleus and the plasma membrane via the linc complex ( linker of nucleoskeleton and cytoskeleton ) , which contains nesprin and sun proteins . sun proteins associate with lamin a and extend their domains into the perinuclear space to contact with the kash domain of nesprins , which are located at the onm and connect with cytoplasmic microtubules , actin , and intermediate filaments . the overexpression of dominant - negative constructs of sun1 and nesprin , which disrupt the connections between the nuclear lamina and the cytoskeleton , not only impairs f - actin polymerization upon tcr stimulation but it also prevents the increased activation of t - cells overexpressing lamin a ( fig .  1 ) . the connection between the linc complex and microtubules is crucial for mtoc orientation during cell polarization and migration of fibroblasts . mtoc translocation to the t cell - apc contact is essential for t cell activation , and expression of a - type lamins in t cells accelerates mtoc repositioning toward the is . although in cytotoxic cd8 t cells mtoc polarization is independent on the centrosomal dissociation from the nuclear envelope , it would be interesting to determine the importance of the linc complex for mtoc translocation in apc - conjugated cd4 t cells . our data indicate that the physical connection between lamin a and the actin cytoskeleton through the linc complex is essential for the optimal stimulation of t cells . membrane - bound adhesion molecules , such as integrins , are connected to the cytoskeleton and with the nuclear lamina through the interactions between the cytoskeleton and the linc complex . the connections between the nucleus and the plasma membrane are essential for the ability of the cells to sense and respond to external stimuli , converting mechanical signals into the activation of specific signaling pathways and the expression of mechanosensitive genes . during t cell activation , the contact between t cells and apcs can produce mechanical signals at the membrane , which could be transmitted to the nucleus after the production of lamin a , modulating t cell functions . accordingly , mechanotransduction has been postulated as a way of regulating t cell activation . it would be interesting to determine whether lamin a regulates integrin - dependent signaling and if it regulates gene expression induced by specific mechanical forces . the transient lamin a / c expression observed upon t cell activation might be essential to regulate these cellular functions . we propose that the increase in lamin a expression after t cell antigen recognition occurs in order to coordinate the process of t cell activation and that the subsequent decrease in lamin a expression would facilitate t cell proliferation and differentiation . in this sense , a low degree of differentiation and/or high levels of proliferation have been associated with a reduction in the expression of a - type lamins during homeostasis and in human malignancies , including leukemias and lymphomas . this decrease in lamins a / c protein expression in hematological malignancies was associated with transcriptional silencing by cpg island promoter hypermethylation . also , expression of tissue specific genes during late stages of differentiation was recently related to an a - type lamins - dependent mechanism , by controlling the tethering of peripheral heterochromatin to the nuclear envelope . somatic cells displaying variable amounts of lamin a expression differ in their dynamics and efficiency during induced pluripotent stem ( ips ) cell induction . the cells that express the higher amounts of lamin a display slower reprogramming and decreased efficiency during ips cell induction . moreover , during reprogramming to ips cells , the initially high levels of lamin a expression are reduced . consistently , in differentiated cells , lamins a / c expression is diminished by exposure of somatic cells to embryonic stem cell extracts , inducing reprogramming of gene expression for pluripotency . thus , we postulate that lamins a / c participate at least in some of the epigenetic changes that occur during immune cell activation . lamins a / c proteins might also be critical regulators in the coordination of t cell migration , an essential process during immune responses . for example , in lmna fibroblasts , cellular migration is altered due to the disruption of the connections between the nucleus and the cytoskeleton , and as a consequence , lmna cells display delayed nuclear and mtoc reorientation during wound healing assays . it would be interesting to determine whether lamin a controls the nuclear position during immune cell migration . during the early nineties , rober and collaborators described the absence of lamins a / c from unstimulated hematopoietic cells from mice , as t and b lymphocytes , granulocytes , macrophages , and monocytes , either isolated from blood or bone marrow . later on , the presence of lamins a / c mrna and protein was observed , respectively , in human monocyte - derived dendritic cells ( dcs ) and rat bone marrow - derived dcs . serum - free differentiation of rat and human dcs was accompanied by acquisition of lamin a / c . primary murine peritoneal macrophages and murine monocyte / macrophage - like cell line ( j774a.1 ) express lamins a / c . interestingly , similarly to what we have observed upon t lymphocyte activation , stimulation of peripheral blood mononuclear cells with concanavalin a resulted in a sharpen increase in the percentage of a - type lamins expressing cells . likewise , treatment of human promyelocytic leukemia hl-60 cells with phorbol esters to trigger their differentiation into macrophage - like cells also enhances the amount of lamins a / c . on the contrary , human primary neutrophils show low - to - negligible amounts of a - type lamins , and differentiation of hl-60 cells into neutrophil - like cells through stimulation with retinoic acid is accompanied by a downregulation of lamins a / c expression . a - type lamins downregulation during neutrophil differentiation seems to be related to the ability of these cells to pass through the vessel walls , since lamin a overexpression in neutrophil - like hl-60 cells impairs the capacity of the cells to transit through micron - scale constrictions . until recently , the presence of lamins a / c in hematopoietic cells was a matter of debate . however , the importance of these proteins in the regulation of the functions of the immune system is gradually being uncovered . another interesting subject that remains largely unexplored is the possibility that other components of the nuclear envelope could control immune cell functions . regarding a - type lamins , it is becoming clearer that their expression is tightly regulated during activation and/or differentiation of immune cells . in t cells , we have recently demonstrated that although resting t lymphocytes do not express lamins a / c , their presence is observed upon antigen recognition , regulating t cell activation threshold . other groups have observed a similar increase in lamins a / c expression in activated macrophages and dcs , while others showed that , in neutrophils , the absence of lamins a / c is crucial for the cellular ability to cross the endothelia . a - type lamins might therefore be important mediators in the coordination of physiological immune responses . together , these evidences suggest that the amount of lamins a / c proteins could underlie some pathological conditions in the immune system .
nuclear lamins a / c control several critical cellular functions , e.g. , chromatin organization , gene transcription , dna replication , dna damage responses , cell cycle progression , cell differentiation , and cell polarization during migration . 
 however , few studies have addressed the role of lamins a / c in the control of the functions of immune cells . 
 recently , we have demonstrated that lamins a / c are induced in t cells upon antigen recognition . 
 lamins a / c enhance t cell responses by coupling the plasma membrane to the nucleus via the linker of nucleoskeleton and cytoskeleton ( linc ) complex and the actin cytoskeleton . here 
 , we discuss the possible physiological relevance and functional context of lamin a / c in t cell activation and propose a model in which lamins a / c are key modulators of immune cell functions .