CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis.

Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis.

Attrition of memory CD8 T cells during sepsis requires LFA-1.

CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69CD25CD62L) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain "unactivated" (i.

CD8 T cells recruited early in mouse polyomavirus infection undergo exhaustion.

Repetitive Ag encounter, coupled with dynamic changes in Ag density and inflammation, imparts phenotypic and functional heterogeneity to memory virus-specific CD8 T cells in persistently infected hosts. For herpesvirus infections, which cycle between latency and reactivation, recent studies demonstrate that virus-specific T cell memory is predominantly derived from naive precursors recruited during acute infection. Whether functional memory T cells to viruses that persist in a nonlatent, low-level infectious state (smoldering infection) originate from acute infection-recruited naive T cells is not known.

MHC class Ib-restricted CD8 T cells differ in dependence on CD4 T cell help and CD28 costimulation over the course of mouse polyomavirus infection.

We recently identified a protective MHC class Ib-restricted CD8 T cell response to infection with mouse polyomavirus. These CD8 T cells recognize a peptide from aa 139-147 of the VP2 viral capsid protein bound to the nonpolymorphic H-2Q9 molecule, a member of the Qa-2 family of β(2)m-associated MHC class Ib molecules. Q9:VP2.

Gamma interferon controls mouse polyomavirus infection in vivo.

Human polyomaviruses are associated with substantial morbidity in immunocompromised patients, including those with HIV/AIDS, recipients of bone marrow and kidney transplants, and individuals receiving immunomodulatory agents for autoimmune and inflammatory diseases. No effective antipolyomavirus agents are currently available, and no host determinants have been identified to predict susceptibility to polyomavirus-associated diseases. Using the mouse polyomavirus (MPyV) infection model, we recently demonstrated that perforin-granzyme exocytosis, tumor necrosis factor alpha (TNF-α), and Fas did not contribute to control of infection or virus-induced tumors.

Heterogeneity among viral antigen-specific CD4+ T cells and their de novo recruitment during persistent polyomavirus infection.

Virus-specific CD4(+) T cells optimize antiviral responses by providing help for antiviral humoral responses and CD8(+) T cell differentiation. Although CD4(+) T cell responses to viral infections that undergo complete clearance have been studied extensively, less is known about virus-specific CD4(+) T cell responses to viruses that persistently infect their hosts. Using a mouse polyomavirus (MPyV) infection model, we previously demonstrated that CD4(+) T cells are essential for recruiting naive MPyV-specific CD8(+) T cells in persistently infected mice.

An MHC class Ib-restricted CD8 T cell response confers antiviral immunity.

Although immunity against intracellular pathogens is primarily provided by CD8 T lymphocytes that recognize pathogen-derived peptides presented by major histocompatibility complex (MHC) class Ia molecules, MHC class Ib-restricted CD8 T cells have been implicated in antiviral immunity. Using mouse polyoma virus (PyV), we found that MHC class Ia-deficient (K(b-/-)D(b-/-)) mice efficiently control this persistently infecting mouse pathogen. CD8 T cell depletion mitigates clearance of PyV in K(b-/-)D(b-/-) mice.

Protection against polyoma virus-induced tumors is perforin-independent.

CD8 T cells are necessary for controlling tumors induced by mouse polyoma virus (PyV), but the effector mechanism(s) responsible have not been determined. We examined the PyV tumorigenicity in C57BL/6 mice mutated in Fas or carrying targeted disruptions in the perforin gene or in both TNF receptor type I and type II genes. Surprisingly, none of these mice developed tumors.