Journal of cellular immunology最新文献

Using four core genotypes (FCG) mice, we have previously shown a larger number of CD4⁺ and CD8⁺ T cells in the spleens of female mice, a sex difference that develops by postnatal day 7 and is retained through adulthood. This difference in splenic T cell number is a consequence of reduced thymic egress and reduced splenic seeding in male mice, caused in part by the male-specific perinatal surge of testosterone, and in part by Sry, which is overexpressed in this model. Here, we used the background strain for FCG mice (C57BL/6J) to ask whether sex influenced actual immunity in the postnatal period. Pups were immunized on postpartum days 1 or 3 with Mycobacterium tuberculosis (Mtb), challenged on day 7 with Mtb purified protein derivative (PPD), and sacrificed on day 8. Subsequent ex vivo challenges of splenocytes showed PPD-stimulated CD8⁺ responses (increased CD8⁺, increased CD8⁺CD44^hi, decreased CD8⁺CD44^hiCD127^-/lo) but no differences between males and females. However, when CD8⁺ T cells were analyzed for IFN-γ and IL-2 production, although there was no sex difference in mono-functional IFN-γ⁺ (100%) or IL-2⁺ (67%), only females (0% of males and 42% of females) produced bi-functional (IFN-γ⁺IL-2⁺) cells. Ex vivo PPD-stimulated responses of other relevant cells from the spleen showed no sex differences in dendritic cells (CD11c⁺CD86⁺IL-6⁺) but females had more (3-fold) IL-6-producing macrophages (F4/80⁺CD86⁺IL-6⁺) and reduced T regulatory cells (CD4⁺CD25⁺Foxp3⁺). We conclude that some sex differences in immunity are evident at one week of age in Mtb immunized mouse pups, with females exhibiting qualitatively superior Mtb-specific immune responses.

Lymphangioleiomyomatosis (LAM) is a rare, female-dominated pulmonary cystic disease. Cysts that develop in LAM are characterized by the presence of smooth muscle-like (LAMCore) cells in the periphery. These cells harbor mutations in Tuberous Sclerosis Complex 1 or 2 (TSC1/2), driving uncontrolled proliferation through the mTORC1 pathway. LAMCore cells originate from an extrapulmonary source. Published data supports the uterine origin of LAMCore cells that metastasize from the uterus to precipitate pulmonary function destruction. Immune evasion is hypothesized to occur to allow seeding of the lungs from the uterus. This evasion specifically involves dysfunctional NK cells to allow aberrant proliferation and migration from the tissue. Single-cell RNA sequencing revealed changes in chemokine and cytokine protein and receptor expression in uterine NK (uNK) and other immune cell populations in a uterine-specific Tsc2-knockout mouse model of LAM. ELISA data revealed increased concentrations of multiple pro-inflammatory cytokines in the sera of aged Tsc2-knockout mice. Flow cytometry, IHC, and functional assays identified compositional and functional insufficiencies of the uNK cells in Tsc2-knockout mice. Furthermore, depletion of NK cells led to the increased development of pulmonary metastases. These data suggest an inflammatory feedback loop affecting multiple cell types including uNK cells, macrophages, and neutrophils. This leads to alterations in immune cell function and composition which allow for LAMCore cell metastasis from the uterine tissue, which may provide a novel mechanism for LAM development.

Influenza and other seasonal respiratory viruses affect millions annually. While age is generally known to be correlated with risk and outcome, the mechanisms underlying these differences, especially in the infected, have been poorly defined. Previous studies have focused primarily on cell-subset shifts in older adults, leaving a gap in understanding of how cytokine responses vary across the full age spectrum. Cytokine data from Luminex assays were compiled from Stanford clinical studies and after batch control filtering, the dataset included 181 healthy individuals (ages 4-97) and 27 symptomatic individuals (mostly confirmed influenza, ages 14-77). Ordinary least squares regression was applied to assess cytokine differences due to infection status, age, and their interaction, with statistical significance defined as p<0.05. The results illustrated that pro-inflammatory cytokines were found to be significantly elevated in infected individuals, with a trend of stronger effects in the young supported by comparison of intercepts between the regressions for the healthy and infected cohorts. The concept of inflammaging was also seen through several biomarkers with significant non-zero slopes in healthy cohorts that were not well-established in prior research. Our findings reveal both expected and novel cytokine behavior in influenza infection across a wide range of ages. By incorporating younger individuals and including age as a continuous variable, the study makes progress towards a deeper understanding of the changes in the immune system and its response to influenza across the lifespan.

Candida auris is a multidrug-resistant fungal pathogen that presents a growing global health challenge, particularly due to its ability to cause invasive bloodstream and deep-seated infections in vulnerable patients. Monoclonal antibody (mAb)-based immunotherapy offers a novel and targeted approach to overcoming the limitations of current antifungal treatments. This commentary highlights the protective efficacy of Candida-specific mAbs, C3.1, 6H1, and 9F2, in in vivo mouse models of disseminated candidiasis. These antibodies target distinct, conserved surface antigens and significantly reduce fungal burden while improving survival outcomes. Their translational potential lies in their specificity, low toxicity, and ability to enhance host immune responses, making them strong candidates for future development as adjunct or alternative therapies for invasive fungal infections in humans.

Background & objectives: The oral cavity is part of the mucosal immune system of the body, embracing all mucosae including lungs, gut and nose. The oral mucosa is the gateway for a plethora of gastrointestinal and respiratory antigens and is capable of mounting a very strong mucosal immune response. Mucosal immunity is structurally and functionally similar in all mucosae and, soluble mediators including cytokines, chemokines, immunoglobulins and other proteins have been well studied in many diseases. However, the roles of mucosal immune cell phenotypes remain less studied causing setbacks in our understanding of the disease pathogeneses.

Methods: We have reviewed the importance of immune phenotyping of the cells in mucosal secretions and the employment of flow cytometry as a reliable tool for this purpose. We previously showed that CD3, CD4, CD8, Th1, and Th2 cells can be detected in stimulated whole mouth fluid (SWMF) in a reproducible and consistent manner, and their ratios may differ from those in the peripheral circulation. We now show for the first time that other salivary lymphocytes Th17, Th22, Tfh, Tregs, NKT, NK, ILC1, ILC2, and ILC3 cells can also be detected and quantified using flow cytometry. PBMC and SWMF from 119 participants were tested by flow cytometry.

Results: Mean frequencies of all the immune cells were detected in a reproducible and consistent manner. In the SWMF the mean frequencies of Th17, Th22, Tfh and NK cells were greater than PBMC. These phenotypes in SWMF showed a negative correlation with PBMC suggesting mucosal origin and specificity.

Conclusions: Our findings strongly suggest that flow cytometry can be employed to detect a wide range of lymphocyte phenotypes in SWMF, a hypotonic secretion. Due to the similarities among the various mucosal secretions, this technique could be explored as a promising tool for understanding immunopathogenesis of infectious and non-infectious diseases using mucosal secretions.

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment by harnessing the host immune system to target malignancies. Melanoma, head and neck squamous cell carcinoma (HNSCC), and triple-negative breast cancer (TNBC) were among the first solid tumors to gain regulatory approval for ICIs due to their immunogenicity and unmet clinical needs. Melanoma exemplifies the success of ICI therapy, with durable responses driven by its high mutation burden and neoantigen landscape, yet both primary and acquired resistance remain major challenges. In contrast, HNSCC demonstrates clinically meaningful but modest responses in the context of a highly immunosuppressive tumor microenvironment, while TNBC derives limited benefit from ICI, often requiring combination strategies to achieve efficacy. Resistance to ICIs arises from complex tumor-intrinsic, microenvironmental, and systemic mechanisms that collectively undermine effective anti-tumor immunity. This review highlights both shared and cancer-specific mechanisms of ICI resistance across melanoma, TNBC and HNSCC. We also discuss emerging strategies, including combination therapies, neoantigen-based vaccines, adoptive T cell therapies, and precision oncology approaches, to overcome resistance and improve clinical outcomes. Together, these insights provide a framework for optimizing immunotherapy and advance durable benefit in these challenging malignancies.

Congenital neutropenia is characterized by a reduced neutrophil count, decreased innate immunity and increased susceptibility to recurrent infections. While congenital neutropenia has various genetic causes, recent studies have linked TCIRG1 mutations to this condition. TCIRG1, a key component of the vacuolar ATPase (V-ATPase) complex, is essential for osteoclast function, but its role in hematopoiesis remains unclear. We previously identified heterozygous TCIRG1 mutations, including R736S, R736C, R736P, and E722D, in individuals with congenital neutropenia. However, the mechanism by which these mutations lead to impaired granulopoiesis remains unknown. To investigate the functional consequences of TCIRG1 mutations, we generated induced pluripotent stem cells (iPSCs) from affected individuals and healthy controls. Using in vitro differentiation protocols, we assessed hematopoietic progenitor formation, proliferation, survival, and neutrophil differentiation. We observed significant defects in myeloid differentiation and increased cell death in patient-derived iPSC lines. CRISPR/Cas9-mediated correction of the R736C mutation restored normal neutrophil differentiation, confirming its pathogenic role. Immunofluorescence analysis revealed reduced expression and altered intracellular localization of the TCIRG1 protein, characterized by a more diffuse cytosolic distribution in the mutant cell lines. Our findings suggest that TCIRG1 mutations impair neutrophil development, likely through structural and functional disruption of the V-ATPase complex. This study provides new insights into the molecular basis of TCIRG1-associated neutropenia and highlights potential avenues for therapeutic intervention.

Introduction: Renal Cell Carcinoma (RCC) is among the most frequently diagnosed malignancies in both genders with over 81,000 estimated cases in 2024. Despite increasing incidence of renal cell carcinomas <4 cm, up to 1/3 of patients diagnosed with RCC exhibit metastatic disease (mRCC) at time of diagnosis. Cytoreductive nephrectomy (CN), a procedure which encompasses the surgical removal of the primary tumor in patients with metastatic disease, was offered upfront as standard of care during the cytokine era; however, as systemic treatment has evolved, the role of CN in mRCC patients has become less clear.

Purpose of review: We sought to review the evolution of CN in mRCC patients from historical treatments through current standard of care considering ongoing clinical trials and perioperative considerations for CN in patients treated with tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI).

Conclusion: CN following immunotherapy is safe and beneficial in appropriately selected patients. The choice to perform CN in patients with mRCC amidst an ever-changing treatment landscape is nuanced. Clinical trial enrollment is critical to refine selection criteria and timing of CN. As treatment options continue to progress, shared decision-making and multidisciplinary collaboration remain paramount in selecting the optimal treatment course for each patient.