Jasmin Herz

PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis

PD-L1 decreases anti-viral CD8+ T cell motility and PD-1 blockade restores motility in the presence of high viral loads.

Peripheral Prepositioning and Local CXCL9 Chemokine-Mediated Guidance Orchestrate Rapid Memory CD8+ T Cell Responses in the Lymph Node

After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against reinfection. Recently, the spatial distribution of memory cells was found to contribute to their protective function. Effector memory CD8+ T cells reside in peripheral tissue sites of initial pathogen encounter, in apparent anticipation of reinfection. Here we show that within lymph nodes (LNs), memory CD8+ T cells were concentrated near peripheral entry portals of lymph-borne pathogens, promoting rapid engagement of infected sentinel macrophages. A feed-forward CXCL9-dependent circuit provided additional chemotactic cues that further increase local memory cell density. Memory CD8+ T cells also produced effector responses to local cytokine triggers, but their dynamic behavior differed from that seen after antigen recognition. These data reveal the distinct localization and dynamic behavior of naive versus memory T cells within LNs and how these differences contribute to host defense.

Migration of cytotoxic lymphocytes in cell cycle permits local MHC I–dependent control of division at sites of viral infection

Virus-specific cytotoxic CD8+ T cells are in cell cycle as they transit from lymphoid tissues to sites of infection.

Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells

Clearance of neurotropic infections is challenging because the CNS is relatively intolerant of immunopathological reactions. Herz et al. use a model of persistent viral infection in mice to demonstrate therapeutic antiviral T cells can purge the CNS infection without causing tissue damage resulting from limited recruitment of inflammatory innate immune cells and conversion of microglia into APCs.

Two-Photon Imaging of Microbial Immunity in Living Tissues

The immune system is highly evolved and can respond to infection throughout the body. Pathogenspecific immune cells are usually generated in secondary lymphoid tissues (e.g., spleen, lymph nodes) and then migrate to sites of infection where their functionality is shaped by the local milieu. Because immune cells are so heavily influenced by the infected tissue in which they reside, it is important that their interactions and dynamics be studied in vivo. Two-photon microscopy is a powerful approach to study host-immune interactions in living tissues, and recent technical advances in the field have enabled researchers to capture movies of immune cells and infectious agents operating in real time. These studies have shed light on pathogen entry and spread through intact tissues as well as the mechanisms by which innate and adaptive immune cells participate in thwarting infections. This review focuses on how two-photon microscopy can be used to study tissue-specific immune responses in vivo, and how this approach has advanced our understanding of host-immune interactions following infection.

c-IAP ubiquitin protein ligase activity is required for 4-1BB signaling and CD8+ memory T-cell survival

Cellular inhibitor of apoptosis proteins (c‐IAP) 1 and 2 are widely expressed ubiquitin protein ligases that regulate a variety of cellular functions, including the sensitivity of T cells to costimulation. 4‐1BB is a TNF receptor family member that signals via a complex that includes TRAF family members and the c‐IAPs to upregulate NF‐κB and ERK, and has been implicated in memory T‐cell survival. Here, we show that effector and memory T cells from mice expressing a dominant negative E3‐inactive c‐IAP2 (c‐IAP2H570A) have impaired signaling downstream of 4‐1BB. When infected with lymphocytic choriomeningitis virus, unlike mice in which c‐IAPs were acutely downregulated by c‐IAP antagonists, the primary response of c‐IAP2H570A mice was normal. However, the number of antigen‐specific CD8+ but not CD4+ T cells declined more rapidly and to a greater extent in c‐IAP2H570A mice than in WT controls. Studies with T‐cell adoptive transfer demonstrated that the enhanced decay of memory cells was T‐cell intrinsic. Thus, c‐IAP E3 activity is required for 4‐1BB coreceptor signaling and maintenance of CD8+ T‐cell memory.