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Activation of self-reactive T cells may depend on aberrant B7 expression on peripheral tissues in mice. Several T-cell mediated autoimmune disease may involve extraordinary expression of costimulatory receptors. Transgenic mice expressing the costimulatory mouse molecule B7-1, a ligand for the CD28 receptor, have been analyzed.

Formulation of two models, instructional and stochastic, is aimed at enunciating the molecular mechanism underlying the contribution of double-positive (DP) thymocytes to the CD4 or CD8 lineage. The stochastic model illustrates independent transition of DP to SP cell, unaffected by T-cell receptor (TCR) specificity for major histocompatibility complex (MHC). The instructional model accounts for cell viability in terms of the potential of TCR, belonging to a quiescent DP cell, to interact with a MHC molecule.

A study of how certain non- or poorly cytopathic viruses can persist in their hosts is reported. The study protocol involved observing the cytotoxic T lymphocyte responses of adult mice to acute infection with the noncytopathic lymphocytic choriomeningitis virus (LCMV). The results showed that some strains of LCMV persist in the host after acute infection without causing lethal immunopathological disease. It seems that the virus induces most of the specific antiviral cytotoxic T lymphocytes, thus causing complete exhaustion of T-cll immunity.

The immune system is successful in protecting the body from viral infection the vast majority of the time. However, some viruses may evade the immune system defenses by a number of different mechanisms. Some viruses invade protected sites, like the brain, where the immune system cannot effectively attack; some viruses down-regulate the cellular expression of both viral antigens and the MHC (major histocompatibility complex) molecules which might present these antigens to the immune system. It is virtually certain that viruses like influenza, against which immunized people are protected by antibodies, can gradually accumulate enough mutations to avoid recognition by these protective antibodies and reinfect the immune population. Researchers have now shown that viruses can also avoid the destruction of infected cells by immune T cells through the selection of new variants. This was demonstrated through the experimental infection of mice with lymphocytic choriomeningitis virus (LCMV). Since the normal repertoire of T cells is so large, it would be difficult to observe the selection of mutant viruses which escape recognition. Therefore, investigators used transgenic mice in which the majority of T cells recognized a single viral antigenic determinant. If a viral variant develops that can escape this immune recognition, it should multiply rapidly and be directly detectable. This is exactly what the researchers found. New variants of LCMV appeared which were altered in the very antigenic determinant used by the T cells for their recognition and destruction. Having evaded this surveillance, the LCMV were free to replicate. Although the experimental conditions were highly artificial, the researchers believe that a similar process might occur during the development of slow, progressive infections such as AIDS. Since HIV, the AIDS virus, does not stimulate the production of protective antibodies, the T cells may be the major barrier to infection. If the rapidly mutating virus can escape this protection, the infection may be free to progress without interruption. (Consumer Summary produced by Reliance Medical Information, Inc.)

NK1.1+ cells found in salivary glands (SG) represent a unique cell population of innate lymphoid cells (ILC) with characteristics of both conventional NK cells and ILC1. Here, we demonstrate that these NK1.1+ cells limit the accumulation and differentiation of virus‐specific tissue‐resident memory CD8+ T cells (TRM cells) in SG of mice infected with lymphocytic choriomeningitis virus (LCMV). The negative regulation of LCMV‐specific CD8+ TRM cells by NK1.1+ cells in SG is independent of NKG2D, NKp46, TRAIL, and perforin. Moreover, analysis of NKp46iCre+Eomesfl/fl mice revealed that Eomes‐dependent conventional NK cells are dispensable for negative regulation. Since the SG are prone to autoimmune reactions, regulation of TRM cells by tissue‐resident ILC may be particularly important to prevent immunopathology in this organ. [ABSTRACT FROM AUTHOR]

During acute viral infections in mice, IL‐7Rα and KLRG1 together are used to distinguish the short‐lived effector cells (SLEC; IL‐7RαloKLRGhi) from the precursors of persisting memory cells (MPEC; IL‐7RαhiKLRG1lo). We here show that these markers can be used to define distinct subsets in the circulation and lymph nodes during the acute phase and in "steady state" in humans. In contrast to the T cells in the circulation, T cells derived from lymph nodes hardly contain any KLRG1‐expressing cells. The four populations defined by IL‐7Rα and KLRG1 differ markedly in transcription factor, granzyme and chemokine receptor expression. When studying renal transplant recipients experiencing a primary hCMV and EBV infection, we also found that after viral control, during latency, Ki‐67‐negative SLEC can be found in the peripheral blood in considerable numbers. Thus, combined analyses of IL‐7Rα and KLRG1 expression on human herpes virus‐specific CD8+ T cells can be used to separate functionally distinct subsets in humans. As a noncycling IL‐7RαloKLRG1hi population is abundant in healthy humans, we conclude that this combination of markers not only defines short‐lived effector cells during the acute response but also stable effector cells that are formed and remain present during latent herpes infections. [ABSTRACT FROM AUTHOR]

Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (Arm) induces an acute infection with rapid virus clearance by CD8+ T cells independently of CD4+ T cell help. Residual viral antigen may, however, persist for a prolonged time. Here, we demonstrate that mice that had been transiently depleted of CD4+ T cells during acute LCMV Arm infection generated high levels of virus‐specific IgG antibodies (Ab) after viral clearance. Robust induction of LCMV‐specific IgG after transient CD4+ T cell depletion was dependent on Fcγ receptors but not on the complement receptors CD21/CD35. In contrast to the potent production of LCMV‐specific IgG, the generation of LCMV‐specific isotype‐switched memory B cells after transient CD4+ T cell depletion was considerably reduced. Moreover, mice depleted of CD4+ T cells during acute infection were strongly impaired in generating a secondary LCMV‐specific B cell response upon LCMV rechallenge. In conclusion, our data indicate that LCMV antigen depots after viral clearance were capable of inducing high levels of virus‐specific IgG. They failed, however, to induce robust virus‐specific B cell memory revealing a previously unappreciated dichotomy of specific Ab production and memory cell formation after priming with residual antigen. Mice transiently depleted of CD4+ T cells during acute LCMV infection generate a robust LCMV‐specific IgG response after viral clearance. In contrast, LCMV‐specific memory B cells (Bm) are poorly induced. Hence, LCMV antigen depots are capable to trigger a strong virus‐specific antibody but not a memory B cell response. [ABSTRACT FROM AUTHOR]

Summary: Memory CD8+ T cells are essential in orchestrating protection from re‐infection. Hallmarks of virus‐specific memory CD8+ T cells are the capacity to mount recall responses with rapid induction of effector cell function and antigen‐independent survival. Growing evidence reveals that even chronic infection does not preclude virus‐specific CD8+ T‐cell memory formation. However, whether this kind of CD8+ T‐cell memory that is established during chronic infection is indeed functional and provides protection from re‐infection is still unclear. Human chronic hepatitis C virus infection represents a unique model system to study virus‐specific CD8+ T‐cell memory formation during and after cessation of persisting antigen stimulation. [ABSTRACT FROM AUTHOR]

Abstract: Cytotoxic T lymphocytes (CTLs) play a key role in the control of lymphocytic choriomeningitis virus (LCMV) infection. In C57BL/6 mice (H‐2b), the CTL response is mainly directed against epitopes from the LCMV glycoprotein (GP) and the nucleoprotein (NP) which represent the two major viral proteins. The role of GP‐ versus NP‐derived epitopes for viral clearance was examined using transgenic (tg) mice ubiquitously expressing LCMV GP and NP, respectively. These mice lack GP‐ or NP‐specific CTLs and show decreased levels of GP‐ or NP‐specific antibodies as a result of tolerance induction. During acute LCMV infection, CTLs specific for GP‐ and NP‐derived epitopes are generated with similar frequencies. Nonetheless, we found that lack of GP‐ but not of NP‐specific CTLs abolished control of acute LCMV infection. In contrast, after high‐dose or chronic LCMV infection, virus elimination was delayed to a similar extent in GP‐ and NP‐tg mice. Thus, immunological tolerance to LCMV antigens differently affects virus clearance in acute and chronic infection settings. In addition, our data reveal that immunodominance of H‐2b‐restricted LCMV‐specific CTL epitopes and their antiviral activity do not strictly correlate. [ABSTRACT FROM AUTHOR]

The salivary glands (SGs) of virus-immune mice contain substantial numbers of tissue-resident memory CD8+ T cells (TRM cells) that can provide immunity to local infections. Integrins regulate entry of activated T cells into nonlymphoid tissues but the molecules that mediate migration of virus-specific CD8+ T cells to the SGs have not yet been defined. Here, we found that polyinosinic-polycytidylic acid (poly(I:C)) strongly promoted the accumulation of P14 TCR-transgenic CD8+ TRM cells in SGs in an α4β1 integrin-dependent manner. After infection with lymphocytic choriomeningitis virus, accumulation of P14 TRM cells in SGs and intestine but not in kidney was also α4 integrin dependent. Blockade of α4β7 by monoclonal antibodies (mAbs) inhibited lymphocytic choriomeningitis virus-induced accumulation of P14 TRM cells in the intestine but not in SGs. In conclusion, our data reveal that α4β1 integrin mediates CD8+ TRM accumulation in SGs and that poly(I:C) can be used to direct activated CD8+ T cells to this organ. [ABSTRACT FROM AUTHOR]