This review discusses situations when the magnitude and function of immune responses to virus infection are influenced by regulatory T cells (Tregs). The focus is on CD4+ CD25+ forkhead box protein 3+ natural Tregs (nTregs). The immune response may be limited in magnitude and efficacy when animals with normal nTreg function are infected with virus. This limitation can be observed both in vitro and in vivo. In the case of herpes simplex virus (HSV), animals depleted of nTregs prior to infection more effectively control the virus. With some virus infections, Treg responses (either nTregs or interleukin-10-dependent adaptive Tregs) appear to contribute to immune dysfunction, accounting for viral persistence and chronic tissue damage. This may occur with hepatitis C virus and some retrovirus infections that include human immunodeficiency virus (HIV). Under other circumstances, the nTreg response is judged to be beneficial, as it may help limit the severity of tissue damage associated with an immunoinflammatory reaction to virus infection. Such a situation occurs in HSV-induced immunopathological lesions in the eye. With HIV, nTregs may help limit chronic immune activation that may precede collapse of the immune system. This review also discusses how virus infections become recognized by nTreg responses and how such responses might be manipulated to increase immunity or to limit virus-induced immunopathology.
Uropod elongation occurs during leukocyte extravasation.
Ocular infection with herpes simplex virus (HSV) sets off an array of events that succeed in clearing virus from the cornea but leaves the tissue with a CD4؉ T-cell-orchestrated chronic inflammatory lesion that impairs vision. We demonstrate that Toll-like receptor (TLR) signaling forms a part of the recognition system that induces the syndrome that eventually culminates in immunopathology. Accordingly, in a comparison of the outcomes of infection in wild-type (WT) mice and those lacking TLR function, it was apparent that the absence of TLR2 and, to a lesser extent, TLR9 resulted in significantly diminished lesions. Similarly, mice lacking the adapter molecule MyD88 were resistant to lesion development, but such animals were also unable to control infection, with most succumbing to lethal encephalitis. The susceptibility of TLR4 ؊/؊ animals was also evaluated. These animals developed lesions, which were more severe, more rapidly than did WT animals. We discuss the possible mechanisms by which early recognition of HSV constituents impacts the subsequent development of immunopathological lesions.
Integrin-mediated cell migration is central to many biologic and pathologic processes. During inflammation, tissue injury results from excessive infiltration and sequestration of activated leukocytes. Recombinant human activated protein C (rhAPC) has been shown to protect patients with severe sepsis, although the mechanism underlying this protective effect remains unclear. Here, we show that rhAPC directly binds to  1 and  3 integrins and inhibits neutrophil migration, both in vitro and in vivo. We found that human APC possesses an Arg-Gly-Asp (RGD) sequence, which is critical for the inhibition. Mutation of this sequence abolished both integrin binding and inhibition of neutrophil migration. In addition, treatment of septic mice with a RGD peptide recapitulated the beneficial effects of rhAPC on survival. Thus, we conclude that leukocyte integrins are novel cellular receptors for rhAPC and the interaction decreases neutrophil recruitment into tissues, providing a potential mechanism by which rhAPC may protect against sepsis. IntroductionMigration of leukocytes to infection sites is vital for pathogen clearance and, thus, host survival. 1 Interaction of cell surface integrins with their counterpart ligands, which are expressed on the endothelial surface, results in the localization and adherence of circulating neutrophils to endothelial cells. This is followed by neutrophil activation and directed migration to sites of infection through the extracellular matrix. An important function of integrins is to concentrate neutrophils at the infection site, ensuring that their immune products and activities remain at this site, while minimizing unnecessary injury to uninfected tissues. Sustained or dysregulated integrin activation, resulting in abnormal neutrophil trafficking, as well as direct damage to the vasculature and the underlying tissue, is known to contribute to sepsis. [2][3][4] Recombinant human activated protein C (rhAPC), the only FDA-approved drug for treating severe sepsis, is a vitamin K-dependent serine protease that is derived from protein C (PC). Activated protein C (APC) is most well known for its anticoagulant functions. Although initial hypotheses to explain its efficacy in preventing severe sepsis centered on the antithrombotic and profibrinolytic functions of rhAPC, 5-8 other agents including antithrombin III and tissue-factor pathway inhibitor, known to have potent effects on such pathways, did not demonstrate the same clinical efficacy in the treatment of severe sepsis as rhAPC, 9,10 suggesting the ability of APC to improve several immunerelated functions independent of its anticoagulant functions. Although regulation of leukocyte migration has been proposed to underlie the protective effects of APC against sepsis, 11-16 the molecular mechanisms of the inhibitory effects of APC have not been demonstrated. Methods ReagentsRecombinant human APC (rhAPC) was obtained from Eli Lilly (Indianapolis, IN). The protein C mutant containing Glu substitution in place of Asp-222 (D222E) was constructed by...
Generating and using regulatory T cells (Tregs) to modulate inflammatory disease represents a valuable approach to therapy but has not yet been applied as a means to control virus-induced immunopathological reactions. In this report, we developed a simplified technique that used unfractionated splenocytes as a precursor population and showed that stimulation under optimized conditions for 5 days with solid-phase anti-CD3 monoclonal antibody in the presence of transforming growth factor  (TGF-) and interleukin-2 could induce up to 90% of CD4 ؉ T cells to become Foxp3 ؉ and able to mediate suppression in vitro. CD11c
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