Human patients with homozygous null mutations in the ICOS gene suffer from recurrent infections due to humoral immune defects. Studies on human patients and mouse models have shown that inducible ...T‐cell co‐stimulator (ICOS)‐deficient individuals cannot form T follicular helper (Tfh) cells, a group of CD4 T cells that migrate into B cell follicles and facilitate germinal center (GC) reactions. ICOS‐induced phosphoinositide 3‐kinase signaling pathways have been shown to play critical roles in Tfh programming, migration of Tfh cells into the GC, and delivery of T cell help during Tfh‐GC B cell conjugation. These processes are also assisted by ICOS‐mediated intracellular calcium mobilization and TANK‐binding kinase 1 signaling. However, ICOS signaling also has stimulatory roles in T regulatory cells and innate lymphoid cells (ILCs), providing another layer of complexity. In this review, we discuss cell‐type‐specific signaling mechanisms utilized by ICOS in Tfh cells, T regulatory cells, and ILCs. Whenever relevant, we compare the roles and signaling pathways of ICOS and CD28. Understanding ICOS signal transduction mechanisms used by distinct immune subsets at different stages of immune responses or disease progression may help improve vaccination protocols, treat autoimmune diseases, and enhance cancer immunotherapy.
ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels ...of ICOS
T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr
-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr
-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.
The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (TFH) and germinal center (GC) reaction. A common signal ...transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in TFH generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4⁺ T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key TFH cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of TFH and suggest that CD28 and ICOS play differential roles during a multistep process of TFH differentiation.
Negative selection of developing T cells plays a significant role in T‐cell tolerance to self‐antigen. This process relies on thymic antigen‐presenting cells which express both self‐antigens and ...cosignaling molecules. Inducible T‐cell costimulator (ICOS) belongs to the CD28 family of cosignaling molecules and binds to ICOS ligand (ICOSL). The ICOS signaling pathway plays important roles in shaping the immune response to infections, but its role in central tolerance is less well understood. Here we show that ICOSL is expressed by subsets of thymic dendritic cells and medullary thymic epithelial cells as well as thymic B cells. ICOS expression is upregulated as T cells mature in the thymus and correlates with T‐cell receptor signal strength during thymic selection. We also provide evidence of a role for ICOS signaling in mediating negative selection. Our findings suggest that ICOS may fine‐tune T‐cell receptor signals during thymic selection contributing to the generation of a tolerant T‐cell population.
We show that inducible T‐cell costimulator (ICOS) expression is upregulated as T cells mature in the thymus and that its ligand is expressed by important thymic antigen‐presenting cell populations that regulate negative selection of autoreactive T cells. We provide evidence of a role for the ICOS–ICOS ligand pathway in fine‐tuning T‐cell receptor signals during thymic selection contributing to the generation of a tolerant T‐cell population. Our observations add an additional layer of complexity to the network of cosignaling molecules potentially involved in sculpting the T‐cell receptor repertoire.
Summary
The Toll‐like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin‐1 receptor and resistance protein (TIR) domain‐containing adaptor inducing ...interferon‐β (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4‐dependent inhibition of allergic airway disease and induction of CD4+ ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild‐type (WT), Trif−/− or Myd88−/− mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF‐dependent and MyD88‐independent. TRIF deficiency diminished the CD4+ ICOS+ T‐cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4+ ICOS+ Foxp3− cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin‐induced CD4+ ICOS+ cells in the TRIF‐dependent inhibition of airway hyper‐responsiveness. Hence, our data demonstrate that stimulation of the TLR4‐TRIF pathway can protect against the development of allergic airway disease and that a TRIF‐dependent adjuvant effect on CD4+ ICOS+ T‐cell responses may be a contributing mechanism.
This manuscript investigates the Toll‐like receptor 4 (TLR4) ‐dependent inhibition of experimental allergic lower airway disease by application to the nasal mucosa of a TLR agonist‐based adjuvant. Our study shows that TRIF, rather than MyD88, signalling downstream of TLR4 is important in the inhibition of experimental asthma in this context and that the TLR4–TRIF‐dependent recruitment of ICOS‐expressing CD4+ T cells to the lungs may contribute to the inhibition of airway hyper‐responsiveness.
To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be ...protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes. Miz-1 exerts this function by directly activating the gene for ribosomal protein L22 (Rpl22), which binds to p53 mRNA and negatively regulates its translation. This mechanism limits p53 expression levels and thus contains its apoptosis-inducing functions in lymphocytes, precisely at differentiation stages in which V(D)J recombination occurs.
Significance V(D)J recombination occurs in lymphoid precursors to enable their maturation, but also induces DNA damage. Thus, it has been proposed that the activity of the tumor suppressor and gatekeeper protein p53 must be controlled during this process to prevent premature induction of apoptosis. In this study, we show that the transcription factor Miz-1 can exert such a function. Miz-1 activates expression of the ribosomal protein Rpl22, which in turn controls the translation of p53 specifically in lymphoid precursors. We propose that this Miz-1–Rpl22–p53 pathway prevents p53 from inducing cell death as a response to V(D)J recombination in lymphoid precursors from both the T-lineage and the B-lineage.
B7-H4, a member of the B7 family of T cell immunomodulatory proteins, has been shown to inhibit T cell responses and neutrophil expansion during bacterial infections. However, the role of B7-H4 in ...the immune response during tumor growth has been unclear. In this study, we examined the host immune responses in B7-H4-deficient (knockout KO) or sufficient (wild-type WT) BALB/cJ mice upon transplantation of murine 4T1 carcinoma cells that had little B7-H4 expression. We reveal that host B7-H4 not only dampens the antitumor Th1 responses, but also inhibits the protumor function of myeloid-derived suppressor cells (MDSC). We observed increased expression of both antitumor immune effectors and protumor MDSC-associated transcripts in 4T1 tumors grown in B7-H4 KO mice compared with those grown in WT hosts. Consistently, MDSCs derived from B7-H4 KO mice suppressed T cell proliferation more potently than their WT counterparts. Although the primary growth of 4T1 tumors in B7-H4 KO hosts was similar to that in WT mice, tumors that had grown in B7-H4 KO hosts grew much slower than those from WT mice when subsequently transplanted into WT hosts. Importantly, this differential tumor growth during the secondary transplantation was abrogated when recipient mice lacked T cells, indicating that the immune environment in B7-H4 KO hosts allowed outgrowth of 4T1 tumors with reduced immune-evasive capacities against T cells. Thus, B7-H4 can inhibit both antitumor T cells and protumor MDSCs, influencing the immune-evasive character of the outgrowing tumors. These factors should be considered if B7-H4 blockade is to be used for cancer immunotherapy.
•A conserved KKKY motif in the cytoplasmic tail of ICOS is necessary and sufficient for ICOS-mediated calcium flux.•ICOS-calcium and ICOS-PI3K signaling can be induced independently of each ...other.•ICOS activates both PLCγ1 and actin remodeling machineries to trigger release of calcium from the intracellular pool.
The inducible costimulator (ICOS) is a T cell costimulatory receptor that plays crucial roles in T cell differentiation and function. So far, ICOS has been shown to activate three signaling components: phosphoinositide 3-kinase (PI3K), intracellular calcium mobilization, and TANK binding kinase 1 (TBK1). By generating a knock-in strain of mice in which the ICOS gene is modified such that the ICOS-mediated PI3K pathway is selectively abrogated while the capacity of ICOS to mobilize intracellular calcium remains intact, we have shown that ICOS-mediated PI3K activation is required for some but not all T cell responses. This suggests that the ICOS-calcium signaling axis may explain some of the PI3K-independent ICOS functions. Further, a recent in vivo imaging study indicated that ICOS-dependent intracellular calcium flux facilitates cognate T cell-B cell interactions within the germinal center. However, how ICOS promotes TCR-mediated calcium flux has not been clear. Here we identified a membrane proximal motif in the cytoplasmic tail of ICOS that is essential for ICOS-assisted calcium signaling and demonstrate that ICOS can induce calcium flux independently of other signaling motifs. We also provide evidence that ICOS potentiates phospholipase Cγ1 (PLCγ1) activation to enhance calcium release from the intracellular pool. In parallel, acute ligation of ICOS without TCR co-engagement leads to activation of small GTPases, RhoA and Cdc42, consistent with the capacity of ICOS to induce actin remodeling. Importantly, interruption of actin dynamics during acute TCR or TCR-ICOS co-ligation severely impairs calcium flux in T cells even in the presence of activated PLCγ1. Thus, ICOS potentiates TCR-induced calcium flux by enhancing PLCγ1 activation and actin remodeling in a coordinated manner.
•ICOS costimulation activates mTOR pathway in activated T cells through PI3K.•ICOS-PI3K-mTOR signaling enhances polysome formation on IL-4 mRNA.•PI3K-mediated ICOS costimulation may facilitate ...delivery of IL-4 to cognate B cells.
The inducible costimulator (ICOS) is highly expressed in follicular helper T (Tfh) cells, a subset of CD4 T cells that migrate into the B cell zone and facilitate germinal center reactions. Although ICOS is known to play a critical role in forming the Tfh cell population during immune responses, its contribution to the effector functions of Tfh cells remains unclear. Using activated mouse splenic CD4 T cells we demonstrate that ICOS assists TCR-mediated signal transduction by potentiating the PI3K-AKT-mTOR signaling cascade that leads to hyper-phosphorylation of p70S6K and 4E-BP1, events that are known to augment cap-dependent mRNA translation. Consequently, ICOS costimulation promotes the formation of polysomes on IL-4 mRNA in a PI3K-dependent manner. Furthermore, we show that the supply of IL-4 becomes a limiting factor for T-dependent B cell activation during in vitro co-culture when the ICOS-PI3K signaling axis is disrupted in T cells. This ICOS costimulation-dependent translational control may ensure targeted delivery of IL-4 to cognate B cells during T–B collaborations in the germinal center.
The incidence of chronic graft-versus-host disease (cGVHD) is on the rise and still the major cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation ...(HCT). Both donor T and B cells contribute to the pathogenesis of cGVHD. Inducible T-cell co-stimulator (ICOS), a potent co-stimulatory receptor, plays a key role in T-cell activation and differentiation. Yet, how ICOS regulates the development of cGVHD is not well understood. Here, we investigated the role of ICOS in cGVHD pathogenesis using mice with germline or regulatory T cell (Treg)-specific ICOS deficiency. The recipients of ICOS
donor grafts had reduced cGVHD compared with wild-type controls. In recipients of ICOS
donor grafts, we observed significant reductions in donor T follicular helper (Tfh), Th17, germinal center B-cell, and plasma cell differentiation, coupled with lower antibody production. Interestingly, Tregs, including follicular regulatory T (Tfr) cells, were also impaired in the absence of ICOS. Using ICOS conditional knockout specific for Foxp3
cells, we found that ICOS was indispensable for optimal survival and homeostasis of induced Tregs during cGVHD. Furthermore, administration of anti-ICOS alleviated cGVHD severity
suppressing T effector cells without affecting Treg generation. Taken together, ICOS promotes T- and B-cell activation and differentiation, which can promote cGVHD development; however, ICOS is critical for the survival and homeostasis of iTregs, which can suppress cGVHD. Hence, ICOS balances the development of cGVHD and could offer a potential target after allo-HCT in the clinic.
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