Impairment of T cell interactions with antigen-presenting cells by immunosuppressive drugs reveals involvement of calcineurin and NF-κB in immunological synapse formation

Foxp3-expressing CD4+CD25+ regulatory T cells (Tregs) constitutively and highly express the immune checkpoint receptor cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose Treg-specific deficiency causes severe systemic autoimmunity. As a key mechanism of Treg-mediated suppression, Treg-expressed CTLA-4 down-regulates the expression of CD80/CD86 costimulatory molecules on antigen-presenting cells (APCs). Here, we show that Treg-expressed CTLA-4 facilitated Treg-APC conjugation and immune synapse formation. The immune synapses thus formed provided a stable platform whereby Tregs were able to deplete CD80/CD86 molecules on APCs by extracting them via CTLA-4–dependent trogocytosis. The depletion occurred even with Tregs solely expressing a mutant CTLA-4 form lacking the cytoplasmic portion required for its endocytosis. The CTLA-4–dependent trogocytosis of CD80/CD86 also accelerated in vitro and in vivo passive transfer of other membrane proteins and lipid molecules from APCs to Tregs without their significant reduction on the APC surface. Furthermore, CD80 down-regulation or blockade by Treg-expressed membrane CTLA-4 or soluble CTLA-4-immunoglobulin (CTLA-4-Ig), respectively, disrupted cis-CD80/programmed death ligand-1 (PD-L1) heterodimers and increased free PD-L1 on dendritic cells (DCs), expanding a phenotypically distinct population of CD80lo free PD-L1hi DCs. Thus, Tregs are able to inhibit the T cell stimulatory activity of APCs by reducing their CD80/CD86 expression via CTLA-4–dependent trogocytosis. This CD80/CD86 reduction on APCs is able to exert dual suppressive effects on T cell immune responses by limiting CD80/CD86 costimulation to naïve T cells and by increasing free PD-L1 available for the inhibition of programmed death-1 (PD-1)–expressing effector T cells. Blockade of CTLA-4 and PD-1/PD-L1 in combination may therefore synergistically hinder Treg-mediated immune suppression, thereby effectively enhancing immune responses, including tumor immunity.

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The Transcription Factor NFAT Exhibits Signal Memory during Serial T Cell Interactions with Antigen-Presenting Cells

Immunity ◽

10.1016/j.immuni.2012.09.012 ◽

2013 ◽

Vol 38 (2) ◽

pp. 237-249 ◽

Cited By ~ 92

Author(s):

Francesco Marangoni ◽

Thomas T. Murooka ◽

Teresa Manzo ◽

Edward Y. Kim ◽

Esteban Carrizosa ◽

...

Keyword(s):

Transcription Factor ◽

T Cell ◽

Antigen Presenting Cells ◽

Cell Interactions ◽

Antigen Presenting ◽

Transcription Factor Nfat

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Searching for immunotherapeutic targets in oncology during immune synapse formation

Problems in oncology ◽

10.37469/0507-3758-2021-67-3-344-349 ◽

2021 ◽

Vol 67 (3) ◽

pp. 344-349

Author(s):

Tatiana Nehaeva ◽

Artem Karpov ◽

Nino Pipia

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Synapse Formation ◽

Immunological Synapse ◽

Cell Receptor ◽

Ligand Molecule ◽

Receptor Ligands ◽

Immune Synapse ◽

Central Cluster ◽

Antigen Presenting

Immunological synapse (IS) is a high-specialized connection between a T-lymphocyte and an antigen-presenting cell (APC), consisting of a cluster of T-cell receptors (TCR) surrounded by a ring of adhesion molecules. It has now been shown that formation of immune synapses is an active and dynamic mechanism that allows T cells to discriminate between potential antigenic ligands. At the first stage T-cell receptor ligands are involved in the external ring of the forming synapse. The movement of these complexes into the central cluster depends on the kinetics of T-cell receptor-ligand molecule interaction. Thus, the formation of a stable central cluster in the immunological synapse is a determining event for T-cell proliferation. The application of effective ways to influence on the IS by introduction into practice of new antitumor drugs and immunological synapse modulators allows to take a new look at the possibilities of tumor immunotherapy.

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