Tissue-resident memory T (TRM) cells are a recently defined subtype of non-recirculating memory T cells with longevity and protective functions in peripheral tissues. As an essential frontline defense against infections, TRM cells have been reported to robustly patrol the tissue microenvironment in malignancies. Accumulating evidence also implicates that TRM cells in the relapse of chronic inflammatory skin diseases such as psoriasis and vitiligo. In light of these developments, this review aims to synthesize these recent findings to enhance our understanding of TRM cell characteristics and actions. Therefore, after providing a brief overview of the general features of the TRM cells, including precursors, homing, retention, and maintenance, we discuss recent insights gained into their heterogeneous functions in skin diseases. Specifically, we explore their involvement in conditions such as psoriasis, vitiligo, fixed drug eruption - dermatological manifestations of drug reactions at the same spot, cutaneous T cell lymphoma, and melanoma. By integrating these diverse perspectives, this review develops a comprehensive model of TRM cell behavior in various skin-related pathologies. In conclusion, our review emphasizes that deciphering the characteristics and mechanisms of TRM cell actions holds potential not only for discovering methods to slow cancer growth but also for reducing the frequency of recurrent chronic inflammation in skin tissue.
Humans ; Skin Diseases/immunology* ; Memory T Cells/immunology* ; Animals ; Vitiligo/immunology* ; Psoriasis/immunology* ; Immunologic Memory

Central memory T (Tcm) cells are a crucial subset in T cell development, playing an important role in long-term immune responses. Tcm cells exhibit strong proliferative capacity, long-term survival characteristics, and re-activation potential, enabling them to rapidly differentiate into effector T cells (Teff) upon antigen re-exposure, thus providing robust immune protection. The function of Tcm cells is regulated by various factors, including antigen exposure, cytokines, and metabolic conditions. A deeper understanding of their metabolic and epigenetic mechanisms under different pathological conditions will contribute to the development of more precise and effective immunotherapeutic strategies. This review elaborates on the origin and characteristics of Tcm cells, as well as their roles in antiviral responses, tumor immunity, and immunotherapy.
Humans ; Memory T Cells/cytology* ; Animals ; Immunologic Memory ; Neoplasms/therapy* ; Immunotherapy

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Cancer immunotherapy including immune checkpoint inhibitors and adoptive cell therapy has gained revolutionary success in the treatment of hematologic tumors; however, it only gains limited success in solid tumors. For example, chimeric antigen receptor T (CAR-T) cell therapy has shown significant effects and potential for curing patients with B-cell malignancies. In contrast, it remains a challenge for CAR-T cell therapy to gain similar success in solid tumors. The anti-tumor effect of endogenous or adoptively transferred tumor-specific T cells depends largely on their differentiation status. T cells at early differentiation stage show better anti-tumor therapeutic effects than fully differentiated effector T cells. In cancer patients, the persistence of tumor-specific T cells with the stem cell memory or precursor phenotype is significantly associated with improved therapeutic outcomes; therefore, adoptively transfered CAR-T cells with stem cell memory and/or central memory is expected to gain better anti-tumor effects. Herein we focused on the in vitro optimized culture and expansion system to obtain CAR-T cells with stem cell memory or central memory phenotype for the review.
Humans ; Immunotherapy, Adoptive/methods* ; Receptors, Chimeric Antigen/genetics* ; Neoplasms/immunology* ; Immunologic Memory ; T-Lymphocytes/immunology* ; Memory T Cells/immunology* ; Animals ; Stem Cells/cytology* ; Cell Differentiation

This study followed up the immune memory after 3-dose revaccination among infants with non-and low-response following primary hepatitis B (HepB) vaccination. About 120 children without self-booster doses were finally included who had anti-HBs<10 mIU/ml (anti-HBs negative) at the time of follow-up, of whom 86 children completed blood sampling and anti-HBs testing. Before the challenge dose, all 86 children were negative for anti-HBs, and the GMC of anti-HBs was<10 mIU/ml. The seropositive conversion rate of anti-HBs was 100% and the GMC of anti-HBs was 886.11 (95%CI: 678.15-1 157.84) mIU/ml after the challenge dose. Compared with those with GMC<7 mIU/ml before the challenge dose, infants with GMC>7 mIU/ml had a higher anti-HBs level after the challenge dose. The β value (95%CI) was 0.82 (0.18-1.46) (P=0.012). Compared with those with GMC<1 000 mIU/ml at primary vaccination, infants with GMC≥1 000 mIU/ml had a higher anti-HBs level after the challenge dose. The β value (95%CI) was 0.78 (0.18-1.38)(P=0.012). The results showed a stronger immune memory was found at 9 years after revaccination among infants with non-and low-response to HepB.
Child ; Humans ; Infant ; Hepatitis B Vaccines ; Immunization, Secondary ; Hepatitis B Surface Antigens ; Immunologic Memory ; Follow-Up Studies ; Vaccination ; Hepatitis B/prevention & control* ; Hepatitis B Antibodies

During virus infection, T cells must be adapted to activation and lineage differentiation states via metabolic reprogramming. Whereas effector CD8⁺ T cells preferentially use glycolysis for their rapid proliferation, memory CD8⁺ T cells utilize oxidative phosphorylation for their homeostatic maintenance. Particularly, enhanced AMP-activated protein kinase (AMPK) activity promotes the memory T cell response through different pathways. However, the level of AMPK activation required for optimal memory T cell differentiation remains unclear. A new metformin derivative, IM156, formerly known as HL156A, has been reported to ameliorate various types of fibrosis and inhibit in vitro and in vivo tumors by inducing AMPK activation more potently than metformin. Here, we evaluated the in vivo effects of IM156 on antigen-specific CD8⁺ T cells during their effector and memory differentiation after acute lymphocytic choriomeningitis virus infection. Unexpectedly, our results showed that in vivo treatment of IM156 exacerbated the memory differentiation of virus-specific CD8⁺ T cells, resulting in an increase in short-lived effector cells but decrease in memory precursor effector cells. Thus, IM156 treatment impaired the function of virus-specific memory CD8⁺ T cells, indicating that excessive AMPK activation weakens memory T cell differentiation, thereby suppressing recall immune responses. This study suggests that metabolic reprogramming of antigen-specific CD8⁺ T cells by regulating the AMPK pathway should be carefully performed and managed to improve the efficacy of T cell vaccine.
AMP-Activated Protein Kinases ; Cell Differentiation ; Fibrosis ; Glycolysis ; Immunologic Memory ; In Vitro Techniques ; Lymphocytic choriomeningitis virus ; Lymphocytic Choriomeningitis ; Memory ; Metformin ; Oxidative Phosphorylation ; T-Lymphocytes

The germinal center reaction is a key event of humoral immunity, providing long-lived immunological memory. Follicular helper T (T(FH)) cells are a specialized subset of CD4⁺ T cells located in the follicles, which help B cells and thus control the germinal center reaction. T(FH) cell development is achieved by multi-step processes of interactions with dendritic cells and B cells along with the coordination of various transcription factors. Since the T helper cell fate decision program is determined by subtle changes in regulatory molecules, fine tuning of these dynamic interactions is crucial for the generation functional T(FH) cells. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulatory molecules for gene expression, which consequently modulate diverse biological functions. In the last decade, the miRNA-mediated regulation network for the germinal center reaction has been extensively explored in T cells and B cells, resulting in the identification of several key miRNA species and their target genes. Here, we review the current knowledge of the miRNA-mediated control of the germinal center reaction, focusing on the aspect of T cell regulation in particular. In addition, we highlight the most important issues related to defining the functional target genes of the relevant miRNAs. We believe that the studies that uncover the miRNA-mediated regulatory axis of T(FH) cell generation and functions by defining their functional target genes might provide additional opportunities to understand germinal center reactions.
B-Lymphocytes ; Dendritic Cells ; Gene Expression ; Germinal Center ; Immunity, Humoral ; Immunologic Memory ; MicroRNAs ; T-Lymphocytes ; T-Lymphocytes, Helper-Inducer* ; Transcription Factors

PURPOSE: In the present study, the protective immunological markers in serum and peripheral blood mononuclear cells (PBMCs) of bacillus Calmette-Guerin (BCG) vaccinated and unvaccinated children were evaluated after vaccination. Further, PBMCs of children with low protective levels were boosted with BCG, Ag85B, and Ag85B peptides to study their booster effects to increase waning BCG induced immunity. MATERIALS AND METHODS: Fifty children from 1 month to 18 years of age were randomized for the study. Blood samples were collected from 27 participants with/without BCG vaccination. Immunological markers (anti-BCG, interferon gamma [IFN-gamma], and adenosine deaminase activity) were assessed in both serum and PBMCs of children. Children with low levels of protective immunological markers were further recruited and their PBMCs were boosted with BCG, Ag85B, and Ag85B peptides. RESULTS: Children in age group of 4-6 years were associated with significantly (p<0.05) higher BCG-specific IgG and IFN-gamma levels compared to those in age group greater than 10 years. Vaccinated children had greater repertoire of immunological memory which on in vitro stimulation with BCG showed increase in BCG-specific response compared to unvaccinated controls. Assessment of booster effects of BCG, Ag85B, and Ag85B peptides in PBMCs of children revealed greater potential of peptides to boost BCG induced immunity compared to BCG and Ag85B. CONCLUSION: To conclude, children within age 4-6 years are associated with high immunological markers which eventually diminish with age thereby suggesting need for booster dose in later years. Mycobacterium tuberculosis peptides along with BCG may be used as attractive candidates to boost such waning BCG induced immunity in children.
Adenosine Deaminase ; Bacillus ; BCG Vaccine ; Child* ; Humans ; Immunoglobulin G ; Immunologic Memory ; Interferon-gamma ; Interferons ; Mycobacterium bovis* ; Mycobacterium tuberculosis ; Peptides* ; Vaccination

OBJECTIVETo detect memory B lymphocyte (Bm) in peripheral blood (PB) of immune-related pancytopenia (IRP).

METHODS86 patients with IRP and 11 health volunteers were enrolled in this study. Bm (CD5⁺ CD19⁺ CD27⁺) and bone marrow mononucleated cell antibodies (BMMNC-Ab) were determined via fluorescence-activated cell sorting, and clinical outcomes of these patients were analyzed.

RESULTS(1)43 initial patients achieved obvious remission in all 52 initial cases after conventional immunosuppression therapy. 16 relapsed patients with IRP received Rituximab (RTX) and 14 cases achieved obvious remission, among which 7 cases were refractory to conventional immunosuppression therapy, 5 cases exhibited obvious remission, and 2 cases did not respond. Other 18 relapsed cases received conventional immunosuppression therapy and 13 cases achieved obvious remission. (1)The level of Bm in PB in 52 initial patients with IRP was(1.81 ± 0.97)%, and no significant difference was observed between the initial patients and health volunteers (1.75 ± 0.55)% (P>0.05). The level of Bm in PB in 34 relapsed patients with IRP was obviously higher than that in the initial IRP patients and health volunteers (P<0.05). Significant difference was observed in the level of Bm in PB in 16 relapsed IRP patients between pre-therapy and post-therapy with RTX (P<0.05). No statistical difference was found between the remission and no-response groups in relapsed patients treated with RTX. RTX regimen produced more effective outcome than conventional immunosuppression therapy, which better eliminated Bm than the latter (P<0.05). Initial patients with IRP who relapsed within a two-year follow-up period had a lower level of Bm in PB compared with un-relapsed patients (P<0.05). Majority of BMMNC- Ab antibodies in relapsed patients were IgG (82.4%) and IgM (69.2%) autoantibodies in patients with initial IRP.

CONCLUSIONThe level of Bm in PB was associated with relapsed patients with IRP. Bm did not respond to conventional immunosuppression therapy,but responded to RTX.

Adolescent ; Adult ; Antibodies, Monoclonal, Murine-Derived ; therapeutic use ; B-Lymphocyte Subsets ; immunology ; Female ; Humans ; Immunologic Memory ; Immunosuppression ; Male ; Middle Aged ; Pancytopenia ; immunology ; therapy ; Recurrence ; Rituximab ; Treatment Outcome ; Young Adult

Qifu-Yin (QFY), a widely used formula of traditional Chinese medicine (TCM) derived from "Jingyue Quanshu", is one of the most commonly used TCM prescriptions for the clinical treatment of Alzheimer disease. The role of advanced glycation end products (AGEs) and its receptor RAGE have attracted increasing attention as the pivotal role of Aβ has been questioned. The present study was designed to test the neuroprotective effects of QFY, and the possible mechanism in AGE-induced Alzheimer model rats. After injection of AGE in the CA3 area of the hippocampus, QFY (8.6, 4.3, and 2.15 g·kg(-1)), and a positive control drug donepezil (2 mg·kg(-1)) were administrated through gastric intubation to rats once daily for thirty consecutive days. Another positive control group was the AGE + anti-RAGE group, which was simultaneously injected with anti-RAGE antibody before AGE treatment. The control group, sham-operated group, as well as the AGE + anti-RAGE group received saline at the same dosage. The Morris water maze test and the step-down passive avoidance test were conducted to evaluate the cognitive function of the rats. The expression of RAGE and NF-κB were assayed by immunohistochemical staining. The levels of Aβ, TNF-α, and IL-1β in the hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that QFY could significantly attenuate the memory impairment induced by AGE, decrease the expressions of RAGE and NF-κB, and reduce the levels of Aβ, TNF-α, and IL-1β in the hippocampus in a dose-dependent manner. Also, the blockage of RAGE could significantly reduce the impairments caused by AGEs. In conclusion, QFY could attenuate AGEs-induced, Alzheimer-like pathophysiological changes. These neuroprotective effects might be related to the RAGE/NF-κB pathway and its anti-inflammatory activity.
Alzheimer Disease ; drug therapy ; metabolism ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Animals ; Anti-Inflammatory Agents ; pharmacology ; therapeutic use ; Brain ; drug effects ; metabolism ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Glycation End Products, Advanced ; adverse effects ; Interleukin-1beta ; metabolism ; Learning ; drug effects ; Magnoliopsida ; Male ; Memory Disorders ; drug therapy ; metabolism ; NF-kappa B ; metabolism ; Phytotherapy ; Plants, Medicinal ; Rats, Sprague-Dawley ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic ; metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha ; metabolism