Durable Interactions of T Cells with T Cell Receptor Stimuli in the Absence of a Stable Immunological Synapse

Abstract Host T cell activation, a key step in obtaining adaptive immunity against pathogens, is initiated by the binding of the T cell receptor to a foreign antigenic peptide presented by the major histocompatibility complex on the surface of an antigen-presenting cell and, consequently, formation of an immunological synapse. Within the immunological synapse, the engagement of the T cell receptor in cooperation with simultaneous ligation of co-stimulatory molecules induces a precisely organized cascade of signaling events and pathways that regulate clonal expansion and differentiation of naïve T cells into effector T cells contributing to pathogen clearance. The biochemical changes that underlie T cell activation and differentiation, however, not only involve proteins but also lipids. In particular, catabolic cleavage of sphingomyelin generating ceramide can substantially influence functional responses in cells of the immune system. Changes in sphingomyelin and ceramide content have been reported to directly impact on membrane physiology, thus modifying signal transmission and interfering with diverse aspects of T cell activity. In this review we will focus on sphingomyelin breakdown/ceramide generation in T cells with regard to their function and development of T cell-mediated immunity.

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INF2 promotes the formation of detyrosinated microtubules necessary for centrosome reorientation in T cells

The Journal of Cell Biology ◽

10.1083/jcb.201202137 ◽

2012 ◽

Vol 198 (6) ◽

pp. 1025-1037 ◽

Cited By ~ 48

Author(s):

Laura Andrés-Delgado ◽

Olga M. Antón ◽

Francesca Bartolini ◽

Ana Ruiz-Sáenz ◽

Isabel Correas ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Immunological Synapse ◽

Cell Receptor ◽

Microtubule Stabilization ◽

Rho Family Gtpases ◽

Tubulin Subunit ◽

Proximal Signaling ◽

Signaling Components

T cell antigen receptor–proximal signaling components, Rho-family GTPases, and formin proteins DIA1 and FMNL1 have been implicated in centrosome reorientation to the immunological synapse of T lymphocytes. However, the role of these molecules in the reorientation process is not yet defined. Here we find that a subset of microtubules became rapidly stabilized and that their α-tubulin subunit posttranslationally detyrosinated after engagement of the T cell receptor. Formation of stabilized, detyrosinated microtubules required the formin INF2, which was also found to be essential for centrosome reorientation, but it occurred independently of T cell receptor–induced massive tyrosine phosphorylation. The FH2 domain, which was mapped as the INF2 region involved in centrosome repositioning, was able to mediate the formation of stable, detyrosinated microtubules and to restore centrosome translocation in DIA1-, FMNL1-, Rac1-, and Cdc42-deficient cells. Further experiments indicated that microtubule stabilization was required for centrosome polarization. Our work identifies INF2 and stable, detyrosinated microtubules as central players in centrosome reorientation in T cells.

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HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

Journal of Virology ◽

10.1128/jvi.01532-16 ◽

2016 ◽

Vol 90 (23) ◽

pp. 10513-10526 ◽

Cited By ~ 7

Author(s):

Jing Deng ◽

Yu-ya Mitsuki ◽

Guomiao Shen ◽

Jocelyn C. Ray ◽

Claudia Cicala ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Immunological Synapse ◽

Cell Receptor ◽

Activation Process ◽

Hiv Envelope

ABSTRACTHIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells.IMPORTANCEThere are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells.

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Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Molecular Biology of the Cell ◽

10.1091/mbc.e08-02-0146 ◽

2008 ◽

Vol 19 (7) ◽

pp. 2802-2817 ◽

Cited By ~ 99

Author(s):

Valarie A. Barr ◽

Kelsie M. Bernot ◽

Sonal Srikanth ◽

Yousang Gwack ◽

Lakshmi Balagopalan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

T Cell Activation ◽

Cell Activation ◽

Immunological Synapse ◽

Cell Receptor ◽

Activated T Cells ◽

Dynamic Movement ◽

Immunological Synapses

The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca2+ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca2+ channel components to existing and newly forming immunological synapses.

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