PARSA LAB
2025
Tissue-specific clonal selection and differentiation of CD4+ T cells during infection
Pathogen-specific CD4⁺ T cells expand and contract during infection,generating memory clones that shape subsequent immune responses. Howdistinct tissue environments influence differentiation and clonal selectionof polyclonal T cells remains unclear. Here we develop Tracking RecentlyActivated Cell Kinetics (TRACK) mice, a dual-recombinase fate-mappingsystem enabling the spatial and temporal labeling of recently activatedCD4⁺ T cells. Using TRACK mice during influenza infection, we observedorgan-specific transcriptional differentiation and clonal selection in lung,mediastinal lymph nodes (medLNs) and spleen. During the effector phase,spleen-derived CD4⁺ T cells adopted a stem-like migratory phenotype,whereas medLN-activated cells differentiated into T follicular helpercells. T cell receptor sequencing showed low clonal overlap betweentissues during the effector response, consistent with distinct antigeniclandscapes. During memory formation, overlap increased between lung-and medLN-derived cells, while splenic clones retained a distinct repertoire.These findings define tissue-dependent mechanisms that shape CD4⁺ T cellfate and clonal architecture.
2022
Newly recruited intraepithelial Ly6A+CCR9+CD4+ T cells protect against enteric viral infection
The intestinal epithelium comprises the body’s largest surface exposed to viruses. Additionally, the gut epithelium hosts a large population of intraepithelial T lymphocytes, or IELs, although their role in resistance against viral infections remains elusive. By fate-mapping T cells recruited to the murine intestine, we observed an accumulation of newly recruited CD4+ T cells after infection with murine norovirus CR6 and adenovirus type-2 (AdV), but not reovirus. CR6- and AdV-recruited intraepithelial CD4+ T cells co-expressed Ly6A and chemokine receptor CCR9, exhibited T helper 1 and cytotoxic profiles, and conferred protection against AdV in vivo and in an organoid model in an IFN-γ-dependent manner. Ablation of the T cell receptor (TCR) or the transcription factor ThPOK in CD4+ T cells prior to AdV infection prevented viral control, while TCR ablation during infection did not impact viral clearance. These results uncover a protective role for intraepithelial Ly6A+CCR9+CD4+ T cells against enteric adenovirus.
Immunity to enteric viruses
Pathogenic enteric viruses are a major cause of morbidity and mortality, particularly among children in devel-oping countries. The host response to enteric viruses occurs primarily within the mucosa, where the intestinalimmune system must balance protection against pathogens with tissue protection and tolerance to harmlesscommensal bacteria and food. Here, we summarize current knowledge in natural immunity to enteric viruses,highlighting specialized features of the intestinal immune system. We further discuss how knowledge of in-testinal anti-viral mechanisms can be translated into vaccine development with particular focus on immuni-zation in the oral route. Research reveals that the intestine is a complex interface between enteric viruses andthe host where environmental factors influence susceptibility and immunity to infection, while viral infectionscan have lasting implications for host health. A deeper mechanistic understanding of enteric anti-viral immu-nity with this broader context can ultimately lead to better vaccines for existing and emerging viruses.
2018
Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling
The cytokine transforming growth factor-β (TGF-β) regulates the development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF-β is not critical for microglia survival but is required for the maintenance of the microglia-specific homeostatic gene signature. Under defined host conditions, circulating monocytes can compete for the microglial niche and give rise to long-lived monocyte-derived macrophages residing in the central nervous system (CNS). Whether monocytes require TGF-β for colonization of the microglial niche and maintenance of CNS integrity is unknown. We found that abrogation of TGF-β signaling in CX3CR1+ monocyte-derived macrophages led to rapid onset of a progressive and fatal demyelinating motor disease characterized by myelin-laden giant macrophages throughout the spinal cord. Tgfbr2-deficient macrophages were characterized by high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. TGF-β is thus crucial for the functional integration of monocytes into the CNS microenvironment.
2016
TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells
Intracerebral levels of Transforming Growth Factor beta (TGFβ) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGFβ responsiveness in EAE by targeting the TGFβ receptor in myeloid cells, determining that Tgfbr2 was specifically targeted in monocyte-derived dendritic cells (moDCs) but not in CNS resident microglia by using bone-marrow chimeric mice. TGFβ responsiveness in moDCs was necessary for the remission phase since LysMCreTgfbr2fl/fl mice developed a chronic form of EAE characterized by severe demyelination and extensive infiltration of activated moDCs in the CNS. Tgfbr2 deficiency resulted in increased moDC IL-12 secretion that skewed T cells to produce IFN-γ, which in turn enhanced the production of moDC-derived reactive oxygen species that promote oxidative damage and demyelination. We identified SNPs in the human NOX2 (CYBB) gene that associated with the severity of MS, and significantly increased CYBB expression was recorded in PBMCs from both MS patients and from MS severity risk allele rs72619425-A carrying individuals. We thus identify a novel myeloid cell-T cell activation loop active in the CNS during chronic disease that could be therapeutically targeted.
BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis
Prolonged infections or adjuvant usage can trigger emergency granulopoiesis (EG), leading to dysregulation in neutrophil blood counts. However, the impact of EG on T and B cell function remains largely unknown. In this study, to address this question, we used a mouse model of neutropenia and studied immune activation after adjuvant administration. The initial neutropenic state fostered an environment of increased dendritic cell activation and T cell–derived IL-17 production. Interestingly, neutropenic lysozyme 2–diphtheria toxin A mice exhibited striking EG and amplified neutrophil recruitment to the lymph nodes (LNs) that was dependent on IL-17–induced prostaglandin activity. The recruited neutrophils secreted a B cell–activating factor that highly accelerated plasma cell generation and antigen-specific antibody production. Reduction of neutrophil functions via granulocyte colony-stimulating factor neutralization significantly diminished plasma cell formation, directly linking EG with the humoral immune response. We conclude that neutrophils are capable of directly regulating T cell–dependent B cell responses in the LN.
2012
Adoptive Transfer of Immunomodulatory M2 Macrophages Prevents Type 1 Diabetes in NOD Mice
Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis depending on their activation phenotype. Autoimmune type 1 diabetes (T1D) is a chronic proinflammatory condition characterized by unresolved destruction of pancreatic islets. Adoptive cell transfer of macrophages with immunosuppressive properties represents a novel immunotherapy for treatment of such chronic autoimmune diseases. We used a panel of cytokines and other stimuli to discern the most effective regimen for in vitro induction of immunosuppressive macrophages (M2r) and determined interleukin (IL)-4/IL-10/transforming growth factor-β (TGF-β) to be optimal. M2r cells expressed programmed cell death 1 ligand-2, fragment crystallizable region γ receptor IIb, IL-10, and TGF-β, had a potent deactivating effect on proinflammatory lipopolysaccharide/interferon-γ–stimulated macrophages, and significantly suppressed T-cell proliferation. Clinical therapeutic efficacy was assessed after adoptive transfer in NOD T1D mice, and after a single transfer of M2r macrophages, >80% of treated NOD mice were protected against T1D for at least 3 months, even when transfer was conducted just prior to clinical onset. Fluorescent imaging analyses revealed that adoptively transferred M2r macrophages specifically homed to the inflamed pancreas, promoting β-cell survival. We suggest that M2r macrophage therapy represents a novel intervention that stops ongoing autoimmune T1D and may have relevance in a clinical setting.