CD160
CD160 antigen precursor (Natural killer cell receptor BY55) (CD160 antigen) [Contains: CD160 antigen, soluble form] [BY55]
Publications[править]
How the measurement of aging biomarkers in peripheral blood T-lymphocytes (PBTLs) is influenced by cell composition is unclear. Here, we collected peripheral blood and isolated CD3 PBTLs from 117 healthy couples between the ages of 21 and 72. Each sample was profiled for Horvath epigenetic clock (DNAm), p16INK4a expression, cytomegalovirus (CMV) seropositivity and 74 mRNA markers of PBTL subtype, differentiation, immune checkpoints, and cytokine production. Correlations between individual aging biomarkers (DNAm or p16INK4a) and PBTL mRNAs were corrected for chronological age, sex, and couple. DNAm measurements correlated with CMV seropositivity as well as PBTL mRNAs indicative of effector function (CD8A, EOMES, TBX21, GZMB), poor proliferative capacity (KLRG1, CD57), differentiation (CD45RO, CD45RA), and immune checkpoints (PDCD1, TIGIT, LAG3, CD160, CD244). In contrast, only three PBTL mRNAs, CD28, CD244, and p14ARF, showed a significant association with p16INK4a. p16INK4a expression also showed a weaker association with immunosenescent PBTL subsets than DNAm in flow cytometry analyses. These data suggest that PBTL composition has a greater influence on DNAm than p16INK4a and link accelerated epigenetic aging to immunosenescent phenotypes.
Keywords
- Aging biomarker
- CMV
- Horvath clock
- Senescence
- T cell
We analyzed gene expression profiles of young and aged mouse CD8 T cells specific for the nucleoprotein (NP) of influenza A/PR8/34 virus. CD8 T cells were stimulated either by the NP antigen expressed in its native form or fused into the herpes virus (HSV)-1 glycoprotein D (gD) protein, which blocks signaling through the immunoinhibitory B and T lymphocyte attenuator (BTLA) and CD160 pathways. We show that NP-specific CD8 T cells from aged mice exhibit numerous differences in gene expression compared to NP-specific CD8 T cells from young mice, including a significant reduction of expression in genes involved in T cell receptor (TcR) and CD28 signaling. We also show that these changes can be reversed in a sub-population (~50%) of the aged mice by a BTLA/CD160 checkpoint blockade. These results suggest that BTLA/CD160 checkpoint blockade has potential value as a vaccine additive to induce better CD8 T cell responses in the aged.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- CD8-Positive T-Lymphocytes
- Female
- GPI-Linked Proteins
- Gene Expression Regulation
- Influenza A virus
- Influenza Vaccines
- Mice
- Mice, Inbred C57BL
- Orthomyxoviridae Infections
- Receptors, Immunologic
- Transcriptome
- Vaccination
Keywords
- BTLA/CD160
- CD8 cells
- aging
- gene expression
- vaccination
Multiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments. Multicolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test. We observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8 T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160) and T cell senescence (CD57, lack of CD28). This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8 T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57 CD28- CD8 T cells was significantly lower in treated myeloma patients when compared to untreated patients. T cells from the bone marrow of myeloma patients were more severely impaired than peripheral T cells. While our data suggest that terminally differentiated cells are preferentially deleted by therapy, immune-checkpoint molecules were still present on T cells supporting the potential of checkpoint inhibitors to reactivate T cells in myeloma patients in combination therapies. However, additional avenues to restore anti-myeloma T cell responses are urgently needed.
MeSH Terms
- Aged
- Blood Cells
- Bone Marrow Cells
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cell Proliferation
- Cellular Senescence
- Female
- Humans
- Immunophenotyping
- Lymphocyte Activation
- Male
- Middle Aged
- Multiple Myeloma
- T-Lymphocyte Subsets
- T-Lymphocytes, Cytotoxic
Keywords
- Bone marrow
- Immune-checkpoint molecules
- Multiple myeloma
- T cell exhaustion
- T cell senescence
Aging is associated with suboptimal CD8 T cell responses to viral infections. It is not clear whether these poor responses are due to environmental influences or quantitative and qualitative changes in the pool of responding CD8 T cells. Our studies demonstrated several deleterious age-related changes in the pool of Ag-specific CD8 T cells that respond to infection. The majority of CD8 T cells from uninfected aged mice was CD44(Hi) and had increased expression of inhibitory receptors including PD1, LAG3, 2B4, and CD160. These aged CD44(Hi) CD8 T cells were transcriptionally similar to exhausted CD8 T cells found during chronic infections. In addition, the number of virus-specific precursors in aged mice prior to infection was decreased up to 10-fold, and many of these Ag-specific precursors had high expression of CD44 and PD1. Finally, TCR transgenic studies demonstrated that the CD44(Hi) Ag-specific CD8 T cells from unimmunized aged and young mice were qualitatively inferior compared with CD44(Lo) CD8 T cells from aged or young donors. Thus, a decrease in precursor frequency as well as qualitative changes of CD8 T cells during aging are directly related to impaired immunity.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Arenaviridae Infections
- CD8-Positive T-Lymphocytes
- Female
- GPI-Linked Proteins
- Hyaluronan Receptors
- Lymphocytic choriomeningitis virus
- Mice
- Programmed Cell Death 1 Receptor
- Receptors, Antigen, T-Cell
- Receptors, Immunologic
- Signaling Lymphocytic Activation Molecule Family