T cell antigen receptor activation and actin cytoskeleton remodeling

Kumari, Sudha; Curado, Silvia; Mayya, Viveka; Dustin, Michael L.

doi:10.1016/j.bbamem.2013.05.004

Cited by 158 publications

(165 citation statements)

References 134 publications

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“…Microvilli are enriched with bundled actin and their stability depends on actin polymerization (1). We therefore treated T cells with the actin-disrupting toxin latrunculin-A (Lat-A), which stabilizes G-actin monomers and prevents actin polymerization (44). SEM images confirmed that most of the microvilli of these lymphocytes disappeared within a 30-min exposure to the Lat-A toxin, both in the case of resting T cells (Fig.…”

Section: Distribution Of Tcrs In Relation To the 3d Topography Of Thementioning

confidence: 80%

Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies

Jung

Riven

Feigelson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

189

232

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Leukocyte microvilli are flexible projections enriched with adhesion molecules. The role of these cellular projections in the ability of T cells to probe antigen-presenting cells has been elusive. In this study, we probe the spatial relation of microvilli and T-cell receptors (TCRs), the major molecules responsible for antigen recognition on the T-cell membrane. To this end, an effective and robust methodology for mapping membrane protein distribution in relation to the 3D surface structure of cells is introduced, based on two complementary superresolution microscopies. Strikingly, TCRs are found to be highly localized on microvilli, in both peripheral blood human T cells and differentiated effector T cells, and are barely found on the cell body. This is a decisive demonstration that different types of T cells universally localize their TCRs to microvilli, immediately pointing to these surface projections as effective sensors for antigenic moieties. This finding also suggests how previously reported membrane clusters might form, with microvilli serving as anchors for specific T-cell surface molecules.T-cell receptor | microvilli | superresolution microscopy | membrane protein clusters | total internal reflection microscopy C irculating leukocytes have a distinctive surface topography dominated by finger-like membranous protrusions, the microvilli (1). Unlike the uniform and regular-sized microvilli found in the intestinal brush border, microvilli on immune cells are highly flexible and dynamic (1-3). Although a role for microvilli in leukocyte capture to blood vessel walls has been demonstrated (4, 5), a physiological role for these projections in the immune response of T cells outside of the vasculature has not yet been established.Going beyond morphological studies requires probing receptor distribution on microvilli and other compartments on leukocyte membranes. The largest obstacles in performing such studies are the thin and short dimensions of microvilli, which require higher resolution than that offered by standard fluorescence microscopy. Therefore, studies of protein distribution in relation to immune cell microvilli have heavily relied on electron microscopy (EM) methods. Indeed, several EM studies of immunogold-labeled surface molecules proposed that some membrane proteins are preferentially localized on microvilli in T cells and macrophages (6-8), whereas other proteins were found to be enriched on the cell body between microvilli (9, 10). Although these earlier studies promoted the idea that microvilli serve as distinctive membranal regions on which certain membrane proteins are selectively localized, they suffered from problems inherent to EM such as sample distortion during the preparation process, as well as artifacts arising from the relatively bulky gold particles and their tendency to stick together (11-13). A fluorescence-based method should be able to overcome these problems.T-cell receptors (TCRs) are membrane protein complexes that recognize antigens as part of the primary steps of adaptiv...

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Section: Distribution Of Tcrs In Relation To the 3d Topography Of Thementioning

confidence: 80%

Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies

Jung

Riven

Feigelson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

189

232

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“…Engagement of the T cell antigen receptor (TCR) by cognate peptide major histocompatibility complex ( pMHC) triggers the assembly of the immunological synapse (IS), a dynamic supra-molecular membrane structure formed at the contact between the T cell and antigen-presenting cell (APC) (Kumari et al, 2014;Fooksman et al, 2010). In addition to organizing signal propagation, the IS likely participates in signal processing required for adequate T cell activation (Acuto et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The T cell IFT20 interactome reveals new players in immune synapse assembly

Galgano

Onnis

Pappalardo

et al. 2017

Journal of Cell Science

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Sustained signalling at the immune synapse (IS) requires the synaptic delivery of recycling endosome-associated T cell antigen receptors (TCRs). IFT20, a component of the intraflagellar transport system, controls TCR recycling to the IS as a complex with IFT57 and IFT88. Here, we used quantitative mass spectrometry to identify additional interaction partners of IFT20 in Jurkat T cells. In addition to IFT57 and IFT88, the analysis revealed new binding partners, including IFT54 (also known as TRAF3IP1), GMAP-210 (also known as TRIP11), Arp2/3 complex subunit-3 (ARPC3), COP9 signalosome subunit-1 (CSN1, also known as GPS1) and ERGIC-53 (also known as LMAN1). A direct interaction between IFT20 and both IFT54 and GMAP-210 was confirmed in pulldown assays. Confocal imaging of antigen-specific conjugates using T cells depleted of these proteins by RNA interference showed that TCR accumulation and phosphotyrosine signalling at the IS were impaired in the absence of IFT54, ARPC3 or ERGIC-53. Similar to in IFT20-deficient T cells, this defect resulted from a reduced ability of endosomal TCRs to polarize to the IS despite a correct translocation of the centrosome towards the antigen-presenting cell contact. Our data underscore the traffic-related role of an IFT20 complex that includes components of the intracellular trafficking machinery in IS assembly.

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“…In addition to the spectrin and ankyrin cyoskeletal systems, actin polymerization has also been shown to play a prominent role in cholesterol dependent signal domain aggregation and synapse formation during T cell activation. 44,[59][60][61][62][63] In turn, we looked at whether blockade of actin polymerization influenced the activating effects of mild heating and ethanol, and found that in both cases actin polymerization was necessary for enhancement of IL-2 production (Fig. 5C).…”

Section: Discussionmentioning

confidence: 99%

A role for the thermal environment in defining co-stimulation requirements for CD4⁺T cell activation

et al. 2015

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Abbreviations: APC, antigen-presenting cell; CD28, cluster of differentiation 28; CD3, cluster of differentiation 3; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CTxB, cholera toxin B subunit; Ct, cycle threshold; ELISA, enzyme-linked immunosorbant assay; EtOH, ethanol; FITC, fluoroisothiocyanate; GM1, monosialotetrahexosylganglioside; IDEAS, imagestream data exploration and analysis software; IL-2, interleukin 2; LA, latrunculin A;MbCD, methyl-b-cyclodextrin; PD-1, Programmed cell death-1; PMA, phorbol 12-myristate 13-acetate; pMHC, peptide-major histocompatibility complexes; qRT-PCR, quantitative reverse transcription polymerase chain reaction; TCR, T cell receptor; TDI, time delay integration; TMA-DPH, trimethylammonium diphenylhexatriene; WBH, whole body hyperthermia.Maintenance of normal core body temperature is vigorously defended by long conserved, neurovascular homeostatic mechanisms that assist in heat dissipation during prolonged, heat generating exercise or exposure to warm environments. Moreover, during febrile episodes, body temperature can be significantly elevated for at least several hours at a time. Thus, as blood cells circulate throughout the body, physiologically relevant variations in surrounding tissue temperature can occur; moreover, shifts in core temperature occur during daily circadian cycles. This study has addressed the fundamental question of whether the threshold of stimulation needed to activate lymphocytes is influenced by temperature increases associated with physiologically relevant increases in temperature. We report that the need for co-stimulation of CD4C T cells via CD28 ligation for the production of IL-2 is significantly reduced when cells are exposed to fever-range temperature. Moreover, even in the presence of sufficient CD28 ligation, provision of extra heat further increases IL-2 production. Additional in vivo and in vitro data (using both thermal and chemical modulation of membrane fluidity) support the hypothesis that the mechanism by which temperature modulates co-stimulation is linked to increases in membrane fluidity and membrane macromolecular clustering in the plasma membrane. Thermally-regulated changes in plasma membrane organization in response to physiological increases in temperature may assist in the geographical control of lymphocyte activation, i.e., stimulating activation in lymph nodes rather than in cooler surface regions, and further, may temporarily and reversibly enable CD4C T cells to become more quickly and easily activated during times of infection during fever.

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T cell antigen receptor activation and actin cytoskeleton remodeling

Cited by 158 publications

References 134 publications

Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies

Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies

The T cell IFT20 interactome reveals new players in immune synapse assembly

A role for the thermal environment in defining co-stimulation requirements for CD4⁺T cell activation

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T cell antigen receptor activation and actin cytoskeleton remodeling

Cited by 158 publications

References 134 publications

Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies

Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies

The T cell IFT20 interactome reveals new players in immune synapse assembly

A role for the thermal environment in defining co-stimulation requirements for CD4+T cell activation

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A role for the thermal environment in defining co-stimulation requirements for CD4⁺T cell activation