ICOS
Inducible T-cell costimulator precursor (Activation-inducible lymphocyte immunomediatory molecule) (CD278 antigen) [AILIM]
Publications[править]
The severity of facial telangiectasia or red veins is associated with many lifestyle factors. However, the genetic predisposition remains unclear. We performed a genome-wide association study (GWAS) on facial telangiectasia in the Rotterdam Study (RS) and tested for replication in two independent cohorts. Additionally, a candidate gene approach with known pigmentation genes was performed. Facial telangiectasia were extracted from standardized facial photographs (collected from 2010-2013) of 2,842 northwestern European participants (median age 66.9, 56.8% female) from the RS. Our GWAS top hits (p-value <10 ) were tested for replication in 460 elderly women of the SALIA cohort and in 576 additional men and women of the RS. Associations of top single-nucleotide polymorphisms (SNPs) with expression quantitative trait loci (eQTL) in various tissues were reviewed (GTEx database) alongside phenotype associations in the UK biobank database. SNP-based associations between known pigmentation genes and facial telangiectasia were tested. Conditional analysis on skin color was additionally performed. Our most significant GWAS signal was rs4417318 (p-value 5.38*10 ), an intergenic SNP on chromosome 12 mapping to the SLC16A7 gene. Other suggestive SNPs tagged genes ZNF211, ZSCAN4, ICOS, and KCNN3; SNP eQTLs and phenotype associations tagged links to the vascular system. However, the top signals did not pass significance in the two replication cohorts. The pigmentation genes KIAA0930, SLCA45A2 and MC1R, were significantly associated with telangiectasia in a candidate gene approach but not independently of skin color. In this GWAS on telangiectasia in a northwestern European population, no genome-wide significant SNPs were found, although suggestive signals indicate genes involved in the vascular system might be involved in telangiectasia. Significantly associated pigmentation genes underline the link between skin color and telangiectasia.
Keywords
- GWAS
- KIAA0930
- MC1R
- SLCA45A2
- SNP
- Telangiectasia
- candidate gene approach
- epidemiology
- genetics
- pigmentation genes
- red veins
- skin aging
Aging is associated with an increased incidence of cancer. One contributing factor could be modulation of immune cells responsible for anti-tumor responses, such as dendritic cells (DCs) and T cells. These immunological changes may also impact the efficacy of cancer immunotherapies in the elderly. The effects of healthy aging on DCs and T cells, and their impact on anti-mesothelioma immune responses, had not been reported. This study examined DCs and T cells in young (2-5 months; equivalent to 16-26 human years) and elderly (20-24 months; equivalent to 60-70 human years) healthy and mesothelioma-bearing C57BL/6J mice. During healthy aging, elderly lymph nodes adopted a regulatory profile, characterized by: (i) increased plasmacytoid DCs, (ii) increased expression of the adenosine-producing enzyme CD73 on CD11c cells, and (iii) increased expression of multiple regulatory markers (including CD73, the adenosine A2B receptor, CTLA-4, PD-1, ICOS, LAG-3, and IL-10) on CD8 and CD4 T cells, compared to lymph nodes from young mice. Although mesotheliomas grew faster in elderly mice, the increased regulatory status observed in healthy elderly lymph node DCs and T cells was not further exacerbated. However, elderly tumor-bearing mice demonstrated reduced MHC-I, MHC-II and CD80 on CD11c cells, and decreased IFN-γ by CD8 and CD4 T cells within tumors, compared to young counterparts, implying loss of function. An agonist CD40 antibody based immunotherapy was less efficient at promoting tumor regression in elderly mice, which may be due to: (i) failure of elderly CD8 T cells to up-regulate perforin, and (ii) increased expression of multiple regulatory markers on CD11c cells and T cells in elderly tumor-draining lymph nodes (including CD73, PD-1, ICOS, LAG-3, and TGF-β). Our findings suggest that checkpoint blockade may improve responses to immunotherapy in elderly hosts with mesothelioma, and warrants further investigation.
Keywords
- aging
- cancer
- dendritic cells
- immunosuppression
- immunotherapy
Premature aging of both CD4 regulatory T (Treg) and CD4 responder-T (Tresp) cells in patients with end-stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible T-cell co-stimulator-positive (ICOS ) and ICOS recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS and ICOS RTE Treg/Tresp cells into ICOS CD31 or ICOS CD31 memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS and ICOS Treg cells in co-culture with autologous Tresp cells. Compared with healthy controls, we found an increased differentiation of ICOS RTE Treg/Tresp cells and ICOS RTE Treg cells through CD31 memory Treg/Tresp cells into CD31 memory Treg/Tresp cells in ESRD and dialysis patients. In contrast, ICOS RTE Tresp cells showed an increased differentiation via ICOS mature naive (MN) Tresp cells into CD31 memory Tresp cells. Thereby, the ratio of ICOS Treg/ICOS Tresp cells was not changed, whereas that of ICOS Treg/ICOS Tresp cells was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS and ICOS RTE Tresp cells proceeded, whereas that of ICOS RTE Treg cells ceased and that of ICOS RTE Treg cells switched to an increased differentiation via ICOS MN Treg cells. Consequently, the ratios of ICOS Treg/ICOS Tresp cells and of ICOS Treg/ICOS Tresp cells decreased significantly, reducing the suppressive activity of Treg cells markedly. Our data reveal that an increased tolerance-inducing differentiation of ICOS and ICOS Treg cells preserves the functional activity of Treg cells in ESRD patients, but this cannot be maintained during long-term renal replacement therapy.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Biomarkers
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Comorbidity
- Female
- Humans
- Immunophenotyping
- Inducible T-Cell Co-Stimulator Protein
- Kidney Failure, Chronic
- Kidney Transplantation
- Lymphocyte Activation
- Male
- Middle Aged
- Renal Dialysis
- T-Lymphocyte Subsets
- Young Adult
Keywords
- T-cell differentiation
- end-stage renal disease
- immunosenescence
- regulatory T cells
- renal replacement therapy
Regulatory T (T ) cells maintain immunological tolerance in steady-state and after immune challenge. Activated T cells can undergo further differentiation into an effector state that highly express genes critical for T cell function, including ICOS, TIGIT and IL-10, although how this process is controlled is poorly understood. Effector T cells also specifically express the transcriptional regulator Blimp-1 whose expression overlaps with many of the canonical markers associated with effector T cells, although not all ICOS TIGIT T cells express Blimp-1 or IL-10. In this study, we addressed the role of Blimp-1 in effector T cell function. Mice lacking Blimp-1 specifically in T cells mature normally, but succumb to a multi-organ inflammatory disease later in life. Blimp-1 is not required for T cell differentiation, with mutant mice having increased numbers of effector T cells, but regulated a suite of genes involved in cell signaling, communication and survival, as well as being essential for the expression of the immune modulatory cytokine IL-10. Thus, Blimp-1 is a marker of effector T cells in all contexts examined and is required for the full functionality of these cells during aging.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cells, Cultured
- Forkhead Transcription Factors
- Immune Tolerance
- Inflammation
- Interleukin-10
- Lymphocyte Activation
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Positive Regulatory Domain I-Binding Factor 1
- Signal Transduction
- T-Lymphocytes, Regulatory
Keywords
- Blimp-1
- Effector regulatory T cells
- IL-10
- Immune infiltration
- Transcription
To cope with immune responses, tumour cells implement elaborate strategies such as adaptive resistance and induction of T-cell exhaustion. T-cell exhaustion has been identified as a state of hyporesponsiveness that arises under continuous antigenic stimulus. Nevertheless, contribution of co-stimulatory molecules to T-cell exhaustion in cancer remains to be better defined. This study explores the role of myeloid leukaemia-derived co-stimulatory signals on CD4 T helper (Th) cell exhaustion, which may limit anti-tumour immunity. Here, CD86 and inducible T-cell co-stimulator ligand (ICOS-LG) co-stimulatory molecules that are found on myeloid leukaemia cells supported Th cell activation and proliferation. However, under continuous stimulation, T cells co-cultured with leukaemia cells, but not with peripheral blood monocytes, became functionally exhausted. These in vitro-generated exhausted Th cells were defined by up-regulation of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitory receptors. They were reluctant to proliferate upon re-stimulation and produced reduced amounts of interleukin-2 (IL-2), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Nonetheless, IL-2 supplementation restored the proliferation capacity of the exhausted Th cells. When the co-stimulation supplied by the myeloid leukaemia cells were blocked, the amount of exhausted Th cells was significantly decreased. Moreover, in the bone marrow aspirates from patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), a subpopulation of Th cells expressing PD-1, TIM-3 and/or LAG3 was identified together with CD86 and/or ICOS-LG myeloid blasts. Collectively, co-stimulatory signals derived from myeloid leukaemia cells possess the capacity to facilitate functional exhaustion in Th cells.
MeSH Terms
- Adult
- Aged
- Antigens, CD
- CD4-Positive T-Lymphocytes
- Cell Line, Tumor
- Coculture Techniques
- Cytokines
- Female
- Hepatitis A Virus Cellular Receptor 2
- Humans
- Immunosenescence
- Leukemia, Myeloid
- Male
- Middle Aged
- Programmed Cell Death 1 Receptor
- Tumor Escape
- Up-Regulation
- Young Adult
Keywords
- T-cell immunoglobulin and mucin domain-containing protein-3
- cancer
- helper T cell
- immune escape
- interleukin-2
- lymphocyte activation gene 3
- programmed cell death 1
ICOSL (B7-H2, CD275), a co-stimulatory molecule of the B7 superfamily, functions as a positive signal in immune response. To investigate whether ICOSL could be released into sera and the possible biological function of soluble ICOS (sICOSL), we generated and characterized a functional anti-human ICOSL monoclonal antibody (mAb), 20B10, and developed a novel enzyme-linked immunosorbent assay (ELISA) based on two anti-human ICOSL antibodies with different epitope specificities. Using the ELISA system, we found that sICOSL in the serum of healthy donors increases in an age-dependent manner and that the matrix metalloproteinase inhibitor (MMPI) could suppress sICOSL production. Together, these data demonstrate that the existence of circulating sICOSL in human serum might play an important role in immunoregulation.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Antibodies, Monoclonal
- Child
- Child, Preschool
- Enzyme-Linked Immunosorbent Assay
- Humans
- Hybridomas
- Inducible T-Cell Co-Stimulator Ligand
- Infant
- Infant, Newborn
- Lymphocyte Activation
- Matrix Metalloproteinase 1
- Mice
- Mice, Inbred BALB C
- Middle Aged
- T-Lymphocytes
- Young Adult
Keywords
- Antibody
- ELISA
- ICOSL
Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice.
MeSH Terms
- Aging
- Animals
- Antibody Formation
- Antigens
- CD28 Antigens
- Immunity, Humoral
- Inducible T-Cell Co-Stimulator Protein
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Ovalbumin
- Peyer's Patches
- Programmed Cell Death 1 Receptor
- T-Lymphocytes, Helper-Inducer
- T-Lymphocytes, Regulatory
Regulatory T cells (Tregs), a subset of CD4( ) T cells, dramatically accumulate with age in humans and mice and contribute to age-related immune suppression. Recently, we showed that a majority of accumulating Tregs in aged mice expressed low levels of CD25, and their accrual is associated with declining levels of IL-2 in aged mice. In this study, we further investigated the origin of CD25(lo) Tregs in aged mice. First, aged Tregs had high expression of neuropilin-1 and Helios, and had a broad Vβ repertoire. Next, we analyzed the gene expression profile of Tregs, naive T cells, and memory T cells in aged mice. We found that the gene expression profile of aged CD25(lo) Tregs were more related to young CD25(lo) Tregs than to either naive or memory T cells. Further, the gene expression profile of aged Tregs was consistent with recently described "effector" Tregs (eTregs). Additional analysis revealed that nearly all Tregs in aged mice were of an effector phenotype (CD44(hi)CD62L(lo)) and could be further characterized by high levels of ICOS and CD69. ICOS contributed to Treg maintenance in aged mice, because in vivo Ab blockade of ICOSL led to a loss of eTregs, and this loss was rescued in Bim-deficient mice. Further, serum levels of IL-6 increased with age and contributed to elevated expression of ICOS on aged Tregs. Finally, Treg accrual was significantly blunted in aged IL-6-deficient mice. Together, our data show a role for IL-6 in promoting eTreg accrual with age likely through maintenance of ICOS expression.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- Apoptosis Regulatory Proteins
- Base Sequence
- Bcl-2-Like Protein 11
- Cell Death
- Cell Survival
- DNA-Binding Proteins
- Gene Expression Profiling
- Hyaluronan Receptors
- Immunologic Memory
- Inducible T-Cell Co-Stimulator Ligand
- Inducible T-Cell Co-Stimulator Protein
- Interleukin-2 Receptor alpha Subunit
- Interleukin-6
- L-Selectin
- Lectins, C-Type
- Membrane Proteins
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neuropilin-1
- Proto-Oncogene Proteins
- Sequence Analysis, DNA
- T-Lymphocytes, Regulatory
- Transcription Factors
Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue, as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2s are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host.
MeSH Terms
- Aging
- Animals
- Diet, High-Fat
- Enzyme Activation
- Inducible T-Cell Co-Stimulator Protein
- Interferon-gamma
- Interleukin-2
- Interleukin-33
- Interleukins
- Intra-Abdominal Fat
- Lectins, C-Type
- Listeria monocytogenes
- Listeriosis
- Lung
- Lymphocyte Activation
- Mice
- Mice, Transgenic
- Nippostrongylus
- Obesity
- Receptors, Immunologic
- Strongylida Infections
- T-Lymphocytes, Regulatory
Although influenza vaccination is recommended for all adults annually, the incidence of vaccine failure, defined as weak or absent increase in neutralizing Ab titers, is increased in the elderly compared with young adults. The T follicular helper cell (Tfh) subset of CD4 T cells provides B cell help in germinal centers and is necessary for class-switched Ab responses. Previous studies suggested a role for circulating Tfh cells (cTfh) following influenza vaccination in adults, but cTfh have not been studied in elderly adults in whom weak vaccine responses are often observed. In this study, we studied cTfh expressing CXCR5 and programmed death-1 (PD-1). cTfh from elderly adults were present at reduced frequency, had decreased in vitro B cell help ability, and had greater expression of ICOS compared with young adults. At 7 d after inactivated influenza vaccination, cTfh correlated with influenza vaccine-specific IgM and IgG responses in young adults but not in elderly adults. In sum, we have identified aging-related changes in cTfh that correlated with reduced influenza vaccine responses. Future rational vaccine design efforts should incorporate Tfh measurement as an immune correlate of protection, particularly in the setting of aging.
MeSH Terms
- Adult
- Age Factors
- Aging
- Antibodies, Viral
- Antibody Formation
- B-Lymphocytes
- CD4-Positive T-Lymphocytes
- Female
- Germinal Center
- Humans
- Immunoglobulin G
- Immunoglobulin M
- Influenza Vaccines
- Male
- Programmed Cell Death 1 Receptor
- Receptors, CXCR5
The immune system consists of multiple preformed and more specific adaptive immune responses, which are all subject to both positive and negative regulation. Programmed cell death protein 1 (PD-1) is a cell surface ligand implicated in the induction of anergy, Inducible T-cell Costimulator (ICOS) plays a stimulatory role in the development of both CD4 and CD8 T-cells, Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) plays a role in inhibitory regulation of T-cell activity, and T cell immunoglobulin and mucin protein 3 (Tim-3) has been described as a negative regulatory molecule in CD4 helper type 1 cells and CD8 cytotoxic type 1 cells. Each of these ligands is induced with T-cell activation allowing greater opportunity to have a regulatory role. Flow cytometry was used to quantitate the expression of PD-1, ICOS, CTLA-4 and Tim-3 in human T-cells from geriatric and younger subjects both at baseline and after in vitro induction by mitogen. The magnitude of expression of the molecules increased significantly on activated blasts after mitogen stimulation compared to their baseline levels in resting cells. The increase in CTLA-4 expressing CD8 T-cells was significantly higher after in vitro induction in older persons, while the increase in cells expressing Tim-3 and PD-1 was significantly reduced. In CD4 T-cells, a greater increase in CTLA-4 expressing cells in older persons was the only difference between the age groups. We found several significant changes in the older individuals in regulatory elements of the adaptive immune system that occur particularly after immune activation. These differences could have ramifications to autoimmunity as well as immunology against infection and tumors.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- CTLA-4 Antigen
- Cells, Cultured
- Flow Cytometry
- Hepatitis A Virus Cellular Receptor 2
- Humans
- Inducible T-Cell Co-Stimulator Protein
- Lymphocyte Activation
- Membrane Proteins
- Programmed Cell Death 1 Receptor
- T-Lymphocytes
- Young Adult