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PubMed2004

Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells.

Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct "central memory" CD62L(+) phenotype.

CD4-Positive T-Lymphocytes↗
PubMed2026

Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC.

PURPOSE: Durvalumab therapy following concurrent chemoradiotherapy (cCRT) improves progression-free survival (PFS) in patients with unresectable locally advanced non-small cell lung cancer. In this prospective observational study, we evaluated the changes in peripheral blood immune cell counts to elucidate the immunologic mechanisms underlying cCRT and durvalumab therapy. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cell (PBMC) samples were collected at four time points: before cCRT, after cCRT, at the start of durvalumab, and 8 weeks after the start of durvalumab, and analyzed by multicolor flow cytometry. RESULTS: Of the 149 enrolled patients, 115 received durvalumab consolidation therapy after cCRT. The median PFS in the overall population was 24.2 months, and the 3-year PFS rate was 38.9%. PBMC analysis showed an increased effector fraction of CD4+ T cells before and after cCRT but no change in CD8+ T cells. Following durvalumab therapy, the effector fraction ratio of CD8+ T cells (CD62Llow CD8+ T cells) increased and positively correlated with increased CD62Llow CD4+ T cells during cCRT. Patients whose proportion of CD62Llow CD4+ T cells exceeded the threshold for cCRT had better PFS than those below the threshold. Patients whose CD62Llow CD8+ T-cell proportion exceeded the threshold after durvalumab therapy showed prolonged PFS compared with those below the threshold. CONCLUSIONS: cCRT promotes an increase in effector CD4+ T cells, and the subsequent increase in CD8+ T cells following durvalumab therapy prolongs PFS. Peripheral blood effector-type CD4+ and CD8+ T cells are potential biomarkers for evaluating the immune status of patients and predicting treatment efficacy.

Humans↗
PubMed1992

Immune cell imbalance in major depressive and panic disorders.

We investigated subsets of peripheral immunologic cells in 12 drug-free patients affected by major depression according to DSM-III-R criteria, and who had recent evidence of somatic diseases. They were compared with 10 drug-free depressives, with 10 patients with panic disorder, and with 12 healthy volunteers, all without somatic disease. The immune subsets were measured by flow cytometry. The results showed that both groups of depressives had the same abnormalities in immune cells compared with the healthy volunteers or the panic disorder patients; in particular they presented a lower number of CD3+, CD8+ and HLA-DR+. The patients with panic attacks did not differ from healthy controls, except for CD4+ cells which were significantly lowered, even in comparison with the depressive groups. These data, although preliminary and in a small sample, suggest that some immune parameters may be influenced by the presence of a major psychiatric disorder.

Adolescent↗
PubMed2026

Shared CD4+ T cell receptor specificity groups in Crohn's disease and ulcerative colitis.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is marked by chronic intestinal inflammation and dysregulated immunity. Although UC and CD affect different areas of the gastrointestinal tract, both diseases share aberrant CD4+ memory T cell responses, with HLA-DRB1 as a major genetic risk factor. HLA-DRB1 encodes MHC class II molecules that influence the CD4+ T cell receptor (TCR) repertoire, yet how these genotypes shape TCR specificity in IBD remains unclear. Here, we genotyped HLA-DRB1 and profiled 3.13 million TCRβ sequences from circulating memory CD4+ T cells in 33 IBD patients (20 UC, 13 CD) and 14 healthy controls. Using the GLIPH2 algorithm, we distilled 468,441 candidates based on CDR3 amino acid motifs into 440 high-confidence TCR specificity groups significantly enriched among individuals sharing HLA-DRB1 alleles. Notably, 5 specificity groups were IBD-enriched and were shared between UC and CD, suggesting common antigen targets in both diseases. We also observed increased frequencies of clonally expanded cytotoxic GZMB+PRF1+ memory CD4+ T cells and KIR+CD8+ T cells in a subset of risk-allele carriers with IBD. These findings elucidate distinct, HLA-linked TCR specificity groups in IBD and provide mechanistic insights that may advance antigen discovery and personalized medicine.

Humans↗
PubMed2026

Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHCII CAR-T cell-treated mice.

In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium-modified (Be-modified) peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirm that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA-seq of lung-resident CCL4/Be tetramer+ CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHCII CAR-T cells as a potentially novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.

Animals↗
PubMed2026

Single-cell capture of on-ART SIV transcription reveals TGF-β-mediated metabolic control of viral latency.

We previously demonstrated that blocking TGF-β with galunisertib, a safe, orally available small drug, reactivated latent SIV in vivo by shifting T cells toward a transitional effector phenotype. Here, we investigated the mechanisms underlying this effect using single-cell RNA sequencing, metabolic profiling, and high-dimensional spectral flow cytometry of samples from SIV-infected, antiretroviral therapy-treated (ART-treated) macaques before and after galunisertib. To characterize virus-transcribing, infected cells during ART, we developed a novel, sensitive SIV Transcripts Capture Assay (SCAP) that detected 127 SIV-expressing cells within lymph node single-cell transcriptome libraries. Galunisertib drove broad metabolic reprogramming in CD4+ T cells, with transcriptional upregulation of inflammatory and mitochondrial biosynthesis pathways, confirmed by Seahorse profiling. Metabolomics revealed increased energy metabolites and amino acids and enhanced metabolic flux without proliferation. SIV transcript-positive cells before galunisertib were metabolically quiescent compared with cells without detectable viral transcripts. After galunisertib, virus-expressing cells showed a dramatic metabolic activation, with upregulation of glycolysis, fatty acid metabolism, and TNF-α signaling. High-dimensional flow cytometry demonstrated effects beyond CD4+ T cells, including fewer tissue-resident memory T cells, but more inflammatory macrophages. In conclusion, SCAP represents a specific tool for characterizing rare SIV-infected cells transcribing virus during ART, and it reveals TGF-β as a key mediator of viral latency in vivo through metabolic suppression.

Virus Latency↗
PubMed2026

Th2 skewing in patients with disseminated coccidioidomycosis.

BACKGROUNDDisseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4+ T cells toward a Th2 phenotype can exist in the context of DCM. Here, we studied a large population to determine the frequency of abnormal Th2 skewing of CD4+ T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this phenotype.METHODSWe collected PBMCs from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4+ T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole-genome sequencing was conducted on 180 individuals who also had cytokine profiling.RESULTSWe found that approximately 25% of patients with DCM had a CD4+ T cell compartment that was abnormally skewed toward a Th2 phenotype, and Th2 skewing was highly correlated with male sex. Coculture of T cells with the IL-4R/IL-13R-blocking antibody dupilumab reduced Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12/IFN-γ axis in several Th2-skewed patients, and we validated one such variant in IFNGR1 as hypomorphic.CONCLUSIONPatients with DCM, especially males, should be screened for Th2 skewing of CD4+ T cells. Patients with Th2 skewing should be additionally screened for genetic defects in the IL-12/IFN-γ axis. Our findings give a mechanistic rationale for blockade of IL-4R in Th2-skewed patients with refractory coccidioidomycosis.FUNDINGNational Institute of Allergy and Infectious Diseases/NIH grants R21 AI149654 and U19 AI166059 and University of California Office of the President grant VFR-19-633386.

Humans↗
PubMed1992

Dual antigenic recognition by cloned human gamma delta T cells.

The function of gamma delta T cells is still elusive. The nature of the antigens that they recognize and the mode of presentation of these antigens are largely unknown. The majority of human peripheral gamma delta T cells bear a V gamma 9/V delta 2 T cell receptor, and display nonclonal reactivity to mycobacteria, without restriction by MHC. It is unknown whether these cells have clonal antigenic specificity as well. Here we describe rheumatoid arthritis-derived V gamma 9/V delta 2 T cell clones, displaying dual antigenic recognition: a nonclonal, MHC-unrestricted recognition of mycobacteria, and a clonal recognition of a short tetanus toxin peptide presented by HLA-DRw53, a nonpolymorphic class II MHC molecule associated with susceptibility to rheumatoid arthritis. This is the first evidence that V gamma 9/V delta 2 T cells can recognize nominal antigenic peptides presented by class II MHC molecules. These results suggest that much like alpha beta T cells, V gamma 9/V delta 2 cells may contribute to the immune response against foreign antigens in an antigen-specific and MHC-restricted manner. The reactivity of these gamma delta T cells to mycobacteria may represent a superantigen-like phenomenon.

Amino Acid Sequence↗
PubMed2026

CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.

Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.

Humans↗
PubMed2025

A targeted CRISPR screen identifies ETS1 as a regulator of HIV-1 latency.

Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between the host cell and HIV-1 latency, we performed a lentiviral CRISPR screen that targeted a set of host cell genes whose expression or activity correlates with HIV-1 expression. We further investigated one of the identified factors - the transcription factor ETS1, and found that it is required for maintenance of HIV-1 latency in both latently infected cell lines and in a primary CD4 T cell latency model. Interestingly, ETS1 played divergent roles in actively infected and latently infected CD4 T cells, with knockout of ETS1 leading to reduced HIV-1 expression in actively infected cells, but increased HIV-1 expression in latently infected cells, indicating that ETS1 can play both a positive and negative role in HIV-1 expression. CRISPR/Cas9 knockout of ETS1 in CD4 T cells from ART-suppressed people with HIV-1 (PWH) confirmed that ETS1 maintains transcriptional repression of the clinical HIV-1 reservoir. Transcriptomic profiling of ETS1-depleted cells from PWH identified a set of host cell pathways involved in viral transcription that are controlled by ETS1 in resting CD4 T cells. In particular, we observed that ETS1 knockout increased expression of the long non-coding RNA MALAT1 that has been previously identified as a positive regulator of HIV-1 expression. Furthermore, the impact of ETS1 depletion on HIV-1 expression in latently infected cells was partially dependent on MALAT1. Additionally, we demonstrate that ETS1 knockout resulted in enhanced abundance of activating modifications (H3K9Ac, H3K27Ac, H3K4me3) on histones located at the HIV-1 long terminal repeat (LTR), indicating that ETS1 regulates the activity of chromatin-targeting complexes at the HIV-1 LTR. Overall, these data demonstrate that ETS1 is an important regulator of HIV-1 latency that impacts HIV-1 expression through repressing MALAT1 expression and by regulating modification of proviral histones.

Proto-Oncogene Protein c-ets-1↗
PubMed1992

Antigen-specific tolerance as a therapy for experimental autoimmune encephalomyelitis.

The effects of neuroantigen-specific tolerance on the induction and effector stages of EAE were examined. Tolerance induced by the i.v. injection of syngeneic splenocytes coupled with purified neuroantigens or encephalitogenic peptides of MBP and PLP using ethylene carbodiimide was extremely effective in both prevention and treatment of acute and relapsing forms of EAE in Lewis rats and SJL/J mice. The unresponsiveness is rapidly-induced, dose-dependent, long-lasting, efficient, MHC class II-restricted, and exquisitely antigen-specific. This procedure targets only effector cells bearing clonotypic receptors specific for the autoantigen/autoepitope and thus does not depend upon the autoimmune response being dominated by a restricted T cell repertoire. Moreover, it does not require that the response to the autoantigen be dominated by recognition of a specific epitope(s) within a particular autoantigen, or even the identification of the specific autoantigen. The results also demonstrate the usefulness of peripheral tolerance induced by antigen-coupled syngeneic splenocytes for identifying the fine specificity of autoimmune T cell responses which appear to change during the progression of relapsing EAE. Thus, this technique offers major advantages over many other currently employed immunoregulatory strategies and is therefore relevant for establishment of therapeutic protocols for the antigen-specific treatment of human T cell-dependent autoimmune disorders.

Animals↗
PubMed1992

Human CD8+ T cell clone regulates autologous CD4+ myelin basic protein specific T cells.

Normal human CD8+ T cell clones were co-isolated from the same culture wells as CD4+ T effector cell clones specific for myelin basic protein (MBP). Microcultures from which the CD8+ clones were isolated initially proliferated weakly to whole MBP and to an MBP peptide spanning residues 90-170. This pattern of response was similar to strongly proliferating wells that yielded CD4+ T cell clones specific for the 90-170 peptide. After repeated stimulation, however, no response to MBP or MBP 90-170 was detected, even though the number of cells increased after stimulation. Phenotyping and TCR analyses revealed the presence of two CD8+, CD4-, IL-2R+ T cell isolates that expressed a single V beta gene (V beta 17) that differed from the CD4+ isolates that uniformly expressed V beta 14. One of these CD8+ clones (C9) inhibited the antigen-driven proliferation of an autologous MBP 90-170 reactive clone but not an autologous clone specific for Herpes simplex virus (HSV), without affecting MHC non-restricted mitogen responses of the same clones. Moreover, C9 did not inhibit heterologous CD4+ T cell clones specific for MBP 1-38 or 90-170. A culture supernatant of the CD8+ clone showed the same pattern but lower levels of inhibition. C9 had mild cytolytic activity when incubated at high ratios with an autologous MBP-specific CD4+ clone. Lysis was blocked completely by anti-MHC class I antibodies, but not by anti-MHC II antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Lymphocytes utilise sialylated surface molecules to accumulate in developing lesions of autoimmune encephalomyelitis.

The accumulation of desialylated radiolabelled normal spleen cells and non-neuroantigen specific CD4 T-lymphocytes was measured in the lumbosacral spinal cord of Lewis rats with autoimmune encephalomyelitis (EAE) induced with myelin basic protein in Freund's adjuvant. The labelled cells were preincubated with sialidase and thoroughly washed prior to intravenous injection into rats exhibiting early clinical signs of EAE. Four hours later, the rats were killed and blood and spinal cord samples were radioassayed. Compared with untreated cells, desialylation markedly reduced the accumulation of both normal spleen cells and memory T-lymphocytes in the spinal cord, despite similar levels of cells being present in the blood. In another experiment, the accumulation of desialylated, macrophage-depleted spleen lymphocytes was measured during the onset, recovery and short-term "relapse" phases of acute EAE. Again, compared with controls the accumulation of desialylated lymphocytes was always significantly less, despite similar numbers of cells in the circulation. Lastly, intravenous injections of sialidase produced delayed onset of both clinical and histological signs in rats with passively-transferred EAE. These data confirm and extend previous findings, using a different animal model, that sialyl residues on the lymphocyte surface are important to the accumulation of such cells at inflammatory sites in the central nervous system. The possible relevance of these findings to human demyelinating disease is discussed.

Animals↗
PubMed1992

Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study.

OBJECTIVE: To evaluate the safety and immunologic and antiviral effects of combination therapy with zidovudine and dideoxycytidine (ddC) in patients with advanced human immunodeficiency virus type 1 (HIV) infection. DESIGN: A phase I/II open-label, dose-ranging study. SETTING: Two AIDS Clinical Trials Group units. PATIENTS: Patients (56) with advanced HIV disease. INTERVENTIONS: Patients were randomly assigned to one of three paired regimens of zidovudine and ddC. We evaluated six dosing regimens, each involving oral administration of the study drugs at 8-hour intervals. MEASUREMENTS: Pharmacokinetics, toxicity, CD4 counts, p24 antigenemia and clinical end points. MAIN RESULTS: The median follow-up period was 40.6 weeks (range, 0.3 to 70 weeks). Neither drug affected the pharmacokinetic profile of the other. Episodes of serious hematologic toxicity were infrequent, occurring in only 17.9% of patients, and did not differ among the regimens (P = 0.15). Severe sensory peripheral neuropathy occurred in two patients (one patient each in regimens 1 and 4). One patient receiving regimen 4 died. The mean maximal increase in CD4 counts exceeded 109 cells/mm3, and 69% of patients receiving combinations containing 300 or 600 mg of zidovudine daily had an increase in CD4 counts of 50 cells/mm3 or greater. Regimens containing 600 mg of zidovudine daily (regimens 2 and 5) were also more likely to result in persistent increases in CD4 counts above pretreatment values than were the two lowest dose regimens (P = 0.003). The decline in CD4 counts was more rapid, and the suppression of the p24 antigenemia was less rapid and less sustained in patients receiving the lowest zidovudine dose alone (regimen 6). The addition of ddC to regimen 6 (regimen 3) resulted in a slower decline in the CD4 counts (P = 0.06). CONCLUSIONS: Combination therapy with zidovudine and ddC at the doses tested was well tolerated and did not result in toxicity. A daily oral dose of 150 mg of zidovudine appeared to produce a suboptimal effect on p24 antigenemia and CD4 counts. Combination therapy with ddC and higher doses of zidovudine produced greater and more persistent effects in patients with advanced HIV infection compared with other study regimens and with the results of previous trials of zidovudine monotherapy.

Adult↗
PubMed1992

Murine B7 antigen provides a sufficient costimulatory signal for antigen-specific and MHC-restricted T cell activation.

We have previously shown that the murine B7 (mB7) molecule, when expressed in Chinese hamster ovary cells in stable fashion, can costimulate with anti-CD3 mAb or Con A to induce T cell activation. We have now derived, by gene transfection, Chinese hamster ovary cell lines that express the I-Ad molecule, either alone or in context with mB7. We have analyzed these transfectants for their capacity to present Ag to murine CD4+ T lymphocytes. I-Ad/mB7-double transfectants were able to stimulate mixed lymphocyte reactions and to present peptide Ag to specific T cells. Chinese hamster ovary cells that expressed only the I-Ad molecule were not able to stimulate T cell proliferation in these systems. Thus, the mB7 protein is a sufficient costimulatory molecule for the physiologic, Ag-dependent/MHC-restricted activation of murine CD4+ T cells. Stimulation of T cell bulk cultures resulted predominantly in the production of IL-2 and not of IL-4. The costimulatory activity of mB7 is not, however, restricted to the IL-2-secreting subset. We have identified one IL-4-secreting T cell clone, CDC35, which is responsive to mB7 triggering. Finally, we present experiments that suggest that mB7 and peptide/MHC complexes need to be expressed on the same cell for optimal induction of T cell activation.

Animals↗
PubMed1992

Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help.

In lymphoid follicles, CD4+ T lymphocytes provide contact-dependent stimuli to B cells that are critical for the generation of specific antibody responses in a process termed Th function. The CD4+ T cell-restricted surface activation protein, 5c8 Ag (T-BAM), has recently been shown to be a component of the contact-dependent helper signal to B cells. To further dissect this process, we utilized a Jurkat T cell lymphoma clone, termed D1.1, that constitutively expresses T-BAM and activates peripheral B cells to express surface CD23 in a contact-dependent mechanism that is inhibited by mAb anti-T-BAM (5c8). Similar to its effect on peripheral B cells, Jurkat D1.1 activates B cells from lymphoid organs, as well as a B cell lymphoma clone, RAMOS 266,4CN 3F10 (RAMOS 266), to up-regulate surface CD23. Interestingly, mAb to the B cell surface molecule, CD40 (mAb G28-5 and B-B20), inhibit D1.1 induced activation of RAMOS 266 and peripheral and lymphoid B cells. In contrast, mAb to CR2 or the adhesion molecules, LFA1, LFA3, or ICAM-1, have little effect. The inhibitory effect of anti-CD40 mAb on B cell activation induced by D1.1 is specific because anti-CD40 potentiates, rather than inhibits, the up-regulation of CD23 on B cells induced by rIL-4. Moreover, cross-linking CD40 molecules by anti-CD40 mAb bound to Fc gamma RII+ (CD32) L cells induces B cell CD23 expression. In vivo, T-BAM-expressing cells are CD4+ T cells that are restricted to lymphoid organs and are localized in the mantle and centrocytic zones of lymphoid follicles and the spleen periarteriolar lymphoid sheath in association with CD40+ B cells. Taken together, these data demonstrate that T-BAM on T cells and CD40 on B cells are involved in contact-dependent T-B help interactions that occur in lymphoid follicles.

Antigens, CD↗