Scott N. Mueller

Post-acute infection sequelae (PAIS), which include diverse immunological alterations and clinical syndromes, represent a significant yet poorly understood phenomenon following acute viral infections. While the host typically resolves acute infections within weeks and develops virus-specific immunity, emerging evidence suggests that long-term symptoms can persist or arise after primary infection recovery. Using the acute lymphocytic choriomeningitis virus (LCMV) infection mouse model, we investigated potential mechanisms underlying immune-related PAIS. By combining mouse infections, different vaccine regimens, and immune monitoring with fluorescence microscopy and 3D image reconstruction of lymphatic tissues, we demonstrated that LCMV-recovered animals exhibit a prolonged immunocompromised state affecting dominantly de novo T cell responses. This is linked to the massive destruction of splenic lymphatic tissue, affecting the compartmentalization of the organ as well as crucial cell–cell contacts necessary for efficient T cell priming. Importantly, LCMV vaccination prevented LCMV-mediated lymphatic tissue destruction and the compromised immunological state. These findings underscore the importance of vaccination in preventing both acute virus infection-mediated pathology and potential PAIS. Our results highlight the complex interplay between virus infections, immune responses, and tissue integrity, challenging the common assumption that hosts fully recover their pre-infection homeostatic health state directly after an acute virus infection is controlled.

The cornea is classically regarded as an immune-privileged tissue. However, recent studies have identified T cells in the healthy human cornea that are absent in specific pathogen-free (SPF) mice. The identity of these T cells, the systemic cues that drive their establishment, and the molecular mechanisms governing their corneal homing remain unknown. Here, we combine multimodal human data with tractable murine models to characterize the cellular basis of corneal immune surveillance. Immunofluorescence staining and confocal imaging of clinically non-inflamed human donor tissues revealed CD3⁺ T cells within the corneal epithelium. Flow cytometry revealed that these cells were predominantly CD8⁺, with a tissue-resident memory T (T _RM ) cell phenotype. In vivo confocal microscopy demonstrated that corneal T cell abundance increased with age, particularly in males, suggesting that accumulation is shaped by cumulative systemic immune experience. Whereas young SPF mice were devoid of corneal T cells, infection with pathogens that do not typically target the cornea induced long-lived T _RM -like CD8⁺ T cells in the cornea. We identified CXCR6 as required for efficient T cell recruitment to the cornea of viral-infected mice. Together, our human and murine data support a model in which systemic immune history, age and biological sex influence local immune surveillance at the human ocular surface.

The central nervous system interprets inflammatory signals in the body and directs the modulation of inflammatory responses by reflexively engaging peripheral sympathetic neurons ^1,2 . This includes sympathetic neurons that innervate the spleen, which can regulate immune functions ^3–5 and modulate inflammation ^6–8 . Yet, it is unclear if neuroimmune interactions involve specialised immunoregulatory sympathetic neurons, and if the immune system can reciprocally regulate peripheral sympathetic neurons to control these responses. Using retrograde tracing and single-cell transcriptomics, we find that spleen-innervating neurons are heterogeneous but do not exhibit a distinct transcriptional program indicative of specialisation for immune communication. However, we report that immune responses induced by pathogens can regulate postganglionic sympathetic neuron functions. Cytokines produced by immune cells downregulate expression of the neurotrophin nerve growth factor in spleen mesenchymal cells, leading to organ-specific sympathetic nerve retraction from the spleen. Concurrently, splenic type I interferon signalling induces inflammatory gene expression in neurons and suppresses neuron excitability. Chemogenetic activation of sympathetic neurons demonstrates an impaired anti-inflammatory capacity in the spleen during infection. These results reveal regulation of sympathetic neuronal functions by the immune system, which could support optimal generation of immune responses against pathogens.

The movement of dendritic cells and T cells within secondary lymphoid organs is critical for the development of adaptive immune responses ^1,2 . Central to this process is the fibroblastic reticular cell (FRC) network, which forms a highly organized conduit system that facilitates the movement of and interactions between dendritic cells and T cells ^3–6 . Previous studies have partly characterized how FRCs support these interactions ^7,8 . However, the molecular mechanisms that operate under physiological conditions remain unknown. Here we show that the viral protein m11, encoded by the herpesvirus murine cytomegalovirus (CMV), inhibits antiviral immunity by targeting the FRC network and interfering with a critical function of cellular CD44. We found that m11 binds to CD44 and established that m11 perturbs the molecular interactions of CD44 with its natural ligand, hyaluronic acid. The interaction of m11 with CD44 impairs the trafficking of dendritic cells within the spleen, thereby impeding efficient priming of naive T cells and the initiation of antiviral CD8 T cell responses. The targeting of CD44 by CMV reveals CD44 as a molecule that is essential to the functioning of the FRC network and uncovers a previously unrecognized stroma-based mechanism that is critical for the generation of effective T cell responses.

Mucosal-associated invariant T cells (MAIT cells) mediate tissue homeostasis and antimicrobial immunity. However, the cells that express major histocompatibility complex (MHC) class I–related protein 1 (MR1) and present microbial vitamin B–derived antigens (VitBAg) to MAIT cells remain unknown. We found that MR1 expression varied across tissues and cell types. Macrophages from the lung and peritoneal cavity expressed the highest levels of MR1 and were the most efficient at capturing and presenting VitBAg to MAIT cells. Expression of MR1 in macrophages was regulated transcriptionally and induced by the tissue environment and microbiota. Depletion of MR1 in macrophages, dendritic cells, and monocytes changed the composition of the microbiota and impaired MAIT cell responses against bacterial infection. We concluded that macrophages are key for MR1 antigen presentation and MAIT cell immunity.

Advances in T cell biology have revealed heterogeneity among T cell populations that is not captured by existing general nomenclature. This issue has caused an ad hoc broadening of core T cell subset definitions and the invention of new subset designations that have not been uniformly delineated. To address this issue, in this Consensus Statement, we propose guidelines that serve three goals. First, they advocate that primary research reports define the experimental basis by which relevant subsets are designated in the methods section of each study. Second, they provide standardized definitions for existing subset designations in popular use, and common experimental criteria for defining each subset are noted. Last, they present an alternative ‘modular nomenclature’ paradigm. The newly proposed modular nomenclature eschews conceptualization of antigen-experienced T cells as belonging to a few idealized subsets, and the nomenclature instead simply indicates individual biological properties present in a T cell population with brief descriptors. Collectively, these guidelines intend to enhance transparency in the literature while facilitating clearer communication of findings and concepts to researchers, students and clinicians.

Exhausted CD8⁺ T (T_EX) cell responses are maintained by precursors of exhausted T (T_PEX) cells that possess high self-renewal and developmental potential. T_PEX cells also drive the proliferative burst of effector T cells upon therapeutic immune checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation and function are not well defined. Here we identify developmental and functional compartmentalization of T_PEX and T_EX cells across secondary lymphoid organs during chronic infection. We show that stem-like CD62L⁺ T_PEX and effector-like CX3CR1⁺ T_EX cells constitute a distinct developmental lineage that is promoted by the lymph node (LN) microenvironment and dependent on the transcription factor KLF2. LNs act as a niche in which migratory dendritic cells provide antigen and costimulatory signals to maintain the proliferative fitness of CD62L⁺ T_PEX cells and generation of CX3CR1⁺ T_EX cells. Moreover, LNs exclusively drive the proliferative burst and systemic dissemination of CX3CR1⁺ T_EX cells during ICB. Thus, our findings identify a unique role for LNs in the maintenance of T cell differentiation and function during systemic chronic infection and ICB therapy.

Fibroblastic reticular cells (FRCs) are specialized fibroblasts that construct secondary lymphoid organs where they provide crucial signals for immune cell homeostasis and migration. While splenic FRCs are thought to support antiviral T cell responses, their role remains unclear. Here, we found that ablation of splenic FRCs impaired virus-specific CD8 ⁺ T cell responses during lymphocytic choriomeningitis virus (LCMV) infection. Immunofluorescence imaging revealed that FRCs promote CD8 ⁺ T cell clustering with type 1 conventional dendritic cells (cDC1) in the T cell zone before migration to the infected marginal zone. Without FRCs, T cells instead clustered with cDC1 and virus-infected cells in the marginal zone, leading to suboptimal priming. Mechanistically, FRCs coordinated early viral replication and the inflammatory milieu for optimal DC activation, and an intact FRC network was crucial for generating effector T cells and maintaining protective memory T cells. Thus, splenic FRCs provide essential lymphoid niches for antiviral T cell responses.