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Welcome to the Fascinating World of Lamins and the Immune System!

Lamin A/C: Guardians of the Nucleus

The mammalian nuclear envelope stands tall as a vital barrier, safeguarding the nucleoplasm from the bustling cytoplasm. At its core lie the crucial components: nuclear pore complexes, the outer and inner nuclear membranes, and the mighty nuclear lamina. Notably, the outer nuclear membrane forms an inseparable bond with the endoplasmic reticulum, while the inner nuclear membrane aligns gracefully with the nuclear lamina (1). Deep within this nucleus fortress, the nuclear lamina forms an intricate filamentous protein layer, primarily starring A- and B-type lamins.

 
 

The mammalian nuclear envelope. Gonzalez JM . Front Biosci 2011

Embark on an Exciting Journey!

 

Prepare to be enthralled as we delve into the captivating realm of lamins! These architectural pillars of the nucleus are encoded by a diverse array of genes: LMNB1 unveils the secrets of lamin B1, LMNB2 unlocks the enigma of lamin B2 and lamin B3 proteins, while LMNA takes the spotlight with major forms like lamin A and C, alongside the alluring lamins A delta10 and C2 1.

 

Unraveling the Mysteries of A-type Lamins (Lamin A/C)

 

Venture into the world of A-type lamins, the captivating type-V intermediate filaments that bestow unwavering mechanical stability upon the nucleus. Their influence reverberates across the regulatory pathways of chromatin structure, DNA repair and replication, nuclear positioning, signal transduction, gene transcription, and the dynamic world of cell proliferation, differentiation, and migration (1,2). These extraordinary functions have been meticulously explored across diverse cell types, yet the enigmatic role of A-type lamins in T-cell-mediated immune responses continues to beckon us

 
 

Lamin A/C expression in PBLs. Red: Lamin A/C. Green: CD4.

Unveiling the Secrets of T-cell Activation

 

The magic of the immune system unfolds with T-cell activation! Witness the spellbinding process that occurs upon the recognition of foreign antigens presented by antigen-presenting cells (APCs). Behold the formation of the immune synapse, a marvelously organized structure that fosters efficient, transient cell-cell communications (3-6). Immune synapse formation and maintenance orchestrate a grand performance of protein complexes, fine-tuning signaling events. Brace yourself for the captivating journey of T-cell receptor (TCR)/CD3 complexes and co-stimulatory receptors congregating at the central supramolecular activation cluster (cSMAC), encircled by the peripheral ring (pSMAC) of actin and integrins.

Immune synapse between a CD4 T-cell and an APC. Reconstruction of the pSMAC . Red: Lamin A/C. Green:Actin. 

Immune synapse between a CD4 T-cell and an APC. Reconstruction of the cSMAC. Green: CD3.

T-cell activation, a spellbinding process, unfurls with the translocation of the microtubule-organizing center (MTOC) towards the T-cell-APC contact. As the MTOC elegantly repositions itself, it orchestrates the polarization of intracellular vesicles to the Immune Synapse (IS) (7-9). These mesmerizing processes stand as pivotal cornerstones, essential for full T-cell activation, and the formation and upkeep of the immune synapse (7). Brace yourself for the magical reorganization of the immune synapse in T-cells, as it conjures the recruitment and activation of intracellular pools of signaling molecules, a dance of molecular wonders (7).

Immune synapse between CD4 T-cells and an APC. Traslocation of the MTOC towards the area of contact.  Green: Tubulin. Blue: APC. Red Actin

The Dance of T-cell Differentiation

 

T-cells orchestrate the defense against microbial pathogens (10). In the arena of peripheral lymphoid organs, cognate CD4+ T-cells spring into action as they proliferate and metamorphose into distinct specialized effector T helper (Th) cells, crucial for the development of adaptive immune responses (11). Witness the tight control of naïve T-cell differentiation, an artful balance that elicits an appropriate host defense, orchestrating immune-mediated inflammation without causing harm to precious tissues. Be mesmerized as Th subsets emerge, each defined by a mesmerizing interplay of surface markers, transcription factors, and effector cytokines, shaping the very nature of the response to pathogens, commensals, and vaccines (10,12-14). Prepare to be enchanted by the enchanting processes that govern Th1 differentiation, triggering the defense against intracellular pathogens with IFNgamma production, while Th2 differentiation unfolds, spurred by extracellular pathogens or allergens with IL-4-dependent STAT6 activation.

 

Lamin A/C: A Tale of T-cell Activation and Differentiation

 

The saga of lamin A/C unfolds as we reveal its transient induction in T-cells upon antigen recognition (16,17). Discover its crucial role in modulating the T-cell activation threshold, ingeniously connecting processes at the plasma membrane, cytoplasm, and nucleus, and deftly coordinating actin dynamics, cellular signaling, gene transcription, and immunological synapse formation (16-18). Prepare to be captivated by its influence on T-cell differentiation, where it augments CD4 T-cell Th1 differentiation in response to pathogen infections, regulating T-bet transcription factor expression and IFNgamma production (19).

 

Unleashing Lamin A/C's Power in Inflammatory Diseases

 

Dive into the realm of inflammatory bowel disease (IBD), a chronic condition that threatens the gastrointestinal tract with unknown origins (20). Unravel the intricate role of naïve CD4 T-cells as they differentiate into Th and Treg cells, playing pivotal roles in the development and protection against IBD. Our exploration aims to decipher the physiological function of lamin A/C in T-cells and investigate whether it holds the key to unlocking therapeutic possibilities for IBD (20).

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Join Us on this Mesmerizing Journey of Discovery!

3D resonstruction of the ileon.   Green: Laminin. Blue: Nucleus. Red Foxp3+ Tregs. Imaris.

3D reconstruction of the colon.  Cyan: Nucleus. Red Foxp3+ Tregs. Imaris

Bibliography

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  2. Andres, V. & Gonzalez, J. M. Role of A-type lamins in signaling, transcription, and chromatin organization. J Cell Biol 187, 945-957, doi:10.1083/jcb.200904124 (2009).

  3. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82-86, doi:10.1038/25764 (1998).

  4. Dustin, M. L. et al. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94, 667-677, doi:S0092-8674(00)81608-6 [pii] (1998).

  5. Wulfing, C. & Davis, M. M. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science 282, 2266-2269 (1998).

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  7. Fooksman, D. R. et al. Functional anatomy of T cell activation and synapse formation. Annu Rev Immunol 28, 79-105, doi:10.1146/annurev-immunol-030409-101308 (2010).

  8. Billadeau, D. D., Nolz, J. C. & Gomez, T. S. Regulation of T-cell activation by the cytoskeleton. Nat Rev Immunol 7, 131-143, doi:10.1038/nri2021 (2007).

  9. Vicente-Manzanares, M. & Sanchez-Madrid, F. Role of the cytoskeleton during leukocyte responses. Nat Rev Immunol 4, 110-122, doi:10.1038/nri1268 (2004).

  10. Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28, 445-489, doi:10.1146/annurev-immunol-030409-101212 (2010).

  11. Kaech, S. M., Wherry, E. J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2, 251-262, doi:10.1038/nri778 (2002).

  12. Szabo, S. J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655-669 (2000).

  13. O'Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098-1102, doi:10.1126/science.1178334 (2010).

  14. van Panhuys, N., Klauschen, F. & Germain, R. N. T-cell-receptor-dependent signal intensity dominantly controls CD4(+) T cell polarization In Vivo. Immunity 41, 63-74, doi:10.1016/j.immuni.2014.06.003 (2014).

  15. Zheng, W. & Flavell, R. A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587-596 (1997).

  16. Gonzalez-Granado, J. M. et al. Nuclear envelope lamin-A couples actin dynamics with immunological synapse architecture and T cell activation. Sci Signal 7, ra37, doi:10.1126/scisignal.2004872 (2014).

  17. Gonzalez-Granado, J. M., Sanchez-Madrid, F., Andres, V. & VanHook, A. M. Science Signaling Podcast: 22 April 2014. Science Signaling 7, pc11-pc11, doi:10.1126/scisignal.2005355 (2014).

  18. Rocha-Perugini, V. & Gonzalez-Granado, J. M. Nuclear envelope lamin-A as a coordinator of T cell activation. Nucleus 5, 396-401, doi:10.4161/nucl.36361 (2014).

  19. Toribio-Fernandez, R. et al. Lamin A/C augments Th1 differentiation and response against vaccinia virus and Leishmania major. Cell Death Dis 9, 9, doi:10.1038/s41419-017-0007-6 (2018).

  20. Toribio-Fernández R et al. Lamin A/C deficiency in CD4+ T-cells enhances regulatory T-cells and prevents inflammatory bowel disease. J Pathol. 2019 Dec;249(4):509-522. doi: 10.1002/path.5332 (2019)

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