Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4+ T Cells during an Immune Response

T cells sense and respond to their local environment at the nanoscale by forming small actin-rich protrusions, called microvilli, which play critical roles in signaling and antigen recognition, particularly at the interface with the antigen presenting cells. However, the mechanisms by which microvilli contribute to cell signaling and activation is largely unknown. Here, we present a tunable engineered system that promotes microvilli formation and T cell signaling via physical stimuli. We discovered that nanoporous surfaces favored microvilli formation, and markedly altered gene expression in T cells and promoted their activation. Mechanistically, confinement of microvilli inside of nanopores leads to size-dependent sorting of membrane-anchored proteins, specifically segregating CD45 phosphatases and T cell receptors (TCR) from the tip of the protrusions when microvilli are confined in 200 nm pores, but not in 400 nm pores. Consequently, formation of TCR nanoclustered hotspots within 200 nm pores, allows sustained and augmented signaling that prompts T cell activation even in the absence of TCR agonists. The synergistic combination of mechanical and biochemical signals on porous surfaces presents a straightforward strategy to investigate the role of microvilli in T cell signaling as well as to boost T cell activation and expansion for application in the growing field of adoptive immunotherapy.

Download Full-text

MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus

Cells ◽

10.3390/cells8111433 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1433 ◽

Cited By ~ 7

Author(s):

Chuang ◽

Tan

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Cell Signaling ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Therapeutic Targets ◽

T Cell Signaling ◽

Systemic Lupus

T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.

Download Full-text

Sphingomyelin Breakdown in T Cells: Role of Membrane Compartmentalization in T Cell Signaling and Interference by a Pathogen

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2019.00152 ◽

2019 ◽

Vol 7 ◽

Cited By ~ 4

Author(s):

Elita Avota ◽

Maria Nathalia de Lira ◽

Sibylle Schneider-Schaulies

Keyword(s):

T Cells ◽

T Cell ◽

Cell Signaling ◽

T Cell Signaling ◽

Membrane Compartmentalization

Download Full-text

Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011150 ◽

2020 ◽

Vol 295 (8) ◽

pp. 2239-2247 ◽

Cited By ~ 5

Author(s):

Jeoung-Eun Park ◽

David D. Brand ◽

Edward F. Rosloniec ◽

Ae-Kyung Yi ◽

John M. Stuart ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tyrosine Kinase ◽

Cell Signaling ◽

Signaling Pathway ◽

T Cell Receptor ◽

Cell Receptor ◽

T Cell Signaling ◽

Tcr Signaling ◽

Cell Signaling Pathway

Multiple observations implicate T-cell dysregulation as a central event in the pathogenesis of rheumatoid arthritis. Here, we investigated mechanisms for suppressing T-cell activation via the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compared 1) T cells from LAIR-1–sufficient and –deficient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, and 3) T cells from mice that contain a CSK transgene susceptible to chemical inhibition. Our results indicated that LAIR-1 engagement by collagen or by complement C1q (C1Q, which contains a collagen-like domain) inhibits TCR signaling by decreasing the phosphorylation of key components in the canonical T-cell signaling pathway, including LCK proto-oncogene SRC family tyrosine kinase (LCK), LYN proto-oncogene SRC family tyrosine kinase (LYN), ζ chain of T-cell receptor–associated protein kinase 70 (ZAP-70), and three mitogen-activated protein kinases (extracellular signal–regulated kinase, c-Jun N-terminal kinase 1/2, and p38). The intracellular region of LAIR-1 contains two immunoreceptor tyrosine-based inhibition motifs that are both phosphorylated by LAIR-1 activation, and immunoprecipitation experiments revealed that Tyr-251 in LAIR-1 binds CSK. Using CRISPR/Cas9-mediated genome editing, we demonstrate that CSK is essential for the LAIR-1–induced inhibition of the human TCR signal transduction. T cells from mice that expressed a PP1 analog–sensitive form of CSK (CskAS) corroborated these findings, and we also found that Tyr-251 is critical for LAIR-1's inhibitory function. We propose that LAIR-1 activation may be a strategy for controlling inflammation and may offer a potential therapeutic approach for managing autoimmune diseases.

Download Full-text

Tofacitinib modulates the VZV-specific CD4+ T cell immune response in vitro in lymphocytes of patients with rheumatoid arthritis

Rheumatology ◽

10.1093/rheumatology/kez175 ◽

2019 ◽

Vol 58 (11) ◽

pp. 2051-2060 ◽

Cited By ~ 10

Author(s):

Giovanni Almanzar ◽

Felix Kienle ◽

Marc Schmalzing ◽

Anna Maas ◽

Hans-Peter Tony ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Granzyme B ◽

Janus Kinase ◽

Cell Immune Response ◽

Dependent Manner ◽

Th1 Response

AbstractObjectiveRA is a chronic inflammatory disease characterized by lymphocyte infiltration and release of inflammatory cytokines. Previous studies have shown that treatment with Janus kinase inhibitors, such as tofacitinib, increased the incidence rate of herpes zoster compared with conventional DMARDs. Therefore, this study aimed to investigate the effect of tofacitinib on the varicella-zoster-virus (VZV)-specific T cell immune response.MethodsThe effect of tofacitinib on the VZV-specific T cell immune response was determined by evaluating the IFNγ production, the proliferative capacity, the VZV-induced differentiation into effector and memory T cells, the expression of activation marker CD69 and helper T cell type 1 (Th1)-characteristic chemokine receptors, such as CXCR3 and CCR5, as well as cytotoxic activity (perforin and granzyme B expression) of CD4+ T cells of patients with RA compared with healthy donors upon stimulation with VZV antigen in vitro.ResultsTofacitinib significantly reduced the IFNγ production, proliferation, activation, and CXCR3 expression of VZV-specific CD4+ T cells in a dose-dependent manner in short- and long-term lymphocyte culture. No effect on the distribution of naive, effectors or memory, or on the expression of perforin or granzyme B by VZV-specific CD4+ T cells was observed.ConclusionThis study showed that tofacitinib significantly modulated the Th1 response to VZV. The poor VZV-specific cellular immune response in patients with RA may be considered in recommendations regarding appropriate vaccination strategies for enhancing the VZV-specific Th1 response.

Download Full-text