Raymond M. Welsh

No one is naive: the significance of heterologous T-cell immunity

Memory T cells that are specific for one virus can become activated during infection with an unrelated heterologous virus, and might have roles in protective immunity and immunopathology. The course of each infection is influenced by the T-cell memory pool that has been laid down by a hosts history of previous infections, and with each successive infection, T-cell memory to previously encountered agents is modified. Here, we discuss evidence from studies in mice and humans that shows the importance of this phenomenon in determining the outcome of infection.

Natural killer cells act as rheostats modulating antiviral T cells

Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection, implying that NK cells have a role in these T-cell-associated diseases. Although direct NK-cell-mediated lysis of virus-infected cells may contribute to antiviral defence during some virus infections—especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans—NK cells have also been suspected of having immunoregulatory functions. For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells. In contrast to MCMV, lymphocytic choriomeningitis virus (LCMV) infection in mice seems to be resistant to any direct antiviral effects of NK cells. Here we examine the roles of NK cells in regulating T-cell-dependent viral persistence and immunopathology in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus doses, NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at medium doses NK cells paradoxically facilitated lethal T-cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.

Attrition of T Cell Memory: Selective Loss of LCMV Epitope–Specific Memory CD8 T Cells following Infections with Heterologous Viruses

Using a variety of techniques, including limiting dilution assays (LDA), intracellular IFNgamma assays, and Db-IgG1 MHC dimer staining to measure viral peptide-specific T cell number and function, we show here that heterologous virus infections quantitatively delete and qualitatively alter the memory pool of T cells specific to a previously encountered virus. We also show that a prior history of a virus infection can alter the hierarchy of the immunodominant peptide response to a second virus and that virus infections selectively reactivate memory T cells with distinct specificities to earlier viruses. These results are consistent with a model for the immune system that accommodates memory T cell populations for multiple pathogens over the course of a lifetime.

Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung

A potent role for memory CD8+ T cells in heterologous immunity was shown with a respiratory mucosal model of viral infection. Memory CD8+ T cells generated after lymphocytic choriomeningitis virus (LCMV) infection were functionally activated in vivo to produce interferon-γ (IFN-γ) during acute infection with vaccinia virus (VV). Some of these antigen-specific memory cells selectively expanded in number, which resulted in modulation of the original LCMV-specific T cell repertoire. In addition, there was an organ-selective compartmental redistribution of these LCMV-specific T cells during VV infection. The presence of these LCMV-specific memory T cells correlated with enhanced VV clearance, decreased mortality and marked changes in lung immunopathology. Thus, the participation of pre-existing memory T cells specific to unrelated agents can alter the dynamics of mucosal immunity and disease course in response to a pathogen.

T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens

We show here that T cell cross-reactivity between heterologous viruses influences the immunodominance of virus-specific CD8+ T cells by two mechanisms. First, T cells specific for cross-reactive epitopes dominate acute responses to viral infections; second, within the memory pool, T cells specific for cross-reactive epitopes are maintained while those specific for non-cross-reactive epitopes are selectively lost. These findings suggest an immunological paradigm in which viral infections shape the available T cell repertoire, causing alterations in the hierarchies of both the primary and memory CD8+ T cell responses elicited by subsequent viral infections. Thus, immunodominance is a function of the hosts previous exposure to unrelated pathogens, and this may have an impact on protective immunity and immunopathology.

Apoptosis in Viral Infections

Publisher Summary Although apoptosis can be induced by a number of stimuli, it has become apparent that there are common connecting themes linking the diverse systems covered in this chapter. Entry into the cell cycle can sensitize cells to apoptosis and abnormal regulation of growth-promoting genes, such as the protooncogenes c-myc and c-fos or of the transcription factor E2F, which can enhance expression of c-myc, results in apoptosis. Lymphocytes responding to viral infection are also more sensitive to apoptosis when in cycle. A second recurring theme is that the tumor suppressor protein p53 will shunt cells into an apoptotic pathway under the conditions of dysregulated expression of growth-promoting genes, and several viruses encode proteins that hind to p53 and interfere with its function. The protective effect of the Bcl-2 protein against apoptosis has been demonstrated repeatedly in viral systems. Apoptosis induced in target cells by either Sindbis or influenza virus infections is greatly inhibited in cells expressing bcl-2. A fourth theme involves the FasITNF receptor system. Activated lymphocytes responding to viral infections express high levels of Fas and are susceptible to apoptosis. Fas is related to the TNF receptor and both are down-regulated when TNF is added to cells. CTL and NK cells encode proteases (granzymes, fragmentins) that induce apoptosis in target cells. It is, therefore, clear that apoptosis plays a major role in viral infections and in the host response to them. Apoptosis is the mechanism, by which many viruses induce cell death and transforming viruses encode proteins that inhibit cellular apoptotic pathways. CTLs, NK cells, and cytotoxic cytokines, all kill virus-infected target cells through apoptotic pathways. In the infected host, T lymphocyte apoptosis plays a role in the natural history of the T cell responses to viral infection.

Attrition of Bystander CD8 T Cells during Virus-Induced T-Cell and Interferon Responses

ABSTRACT Experiments designed to distinguish virus-specific from non-virus-specific T cells showed that bystander T cells underwent apoptosis and substantial attrition in the wake of a strong T-cell response. Memory CD8 T cells (CD8+ CD44hi) were most affected. During acute viral infection, transgenic T cells that were clearly defined as non-virus specific decreased in number and showed an increase in apoptosis. Also, use of lymphocytic choriomeningitis virus (LCMV) carrier mice, which lack LCMV-specific T cells, showed a significant decline in non-virus-specific memory CD8 T cells that correlated to an increase in apoptosis in response to the proliferation of adoptively transferred virus-specific T cells. Attrition of T cells early during infection correlated with the alpha/beta interferon (IFN-α/β) peak, and the IFN inducer poly(I:C) caused apoptosis and attrition of CD8+CD44hi T cells in normal mice but not in IFN-α/β receptor-deficient mice. Apoptotic attrition of bystander T cells may make room for the antigen-specific expansion of T cells during infection and may, in part, account for the loss of T-cell memory that occurs when the host undergoes subsequent infections.

Heterologous immunity between viruses.

Summary:  Immune memory responses to previously encountered pathogens can sometimes alter the immune response to and the course of infection of an unrelated pathogen by a process known as heterologous immunity. This response can lead to enhanced or diminished protective immunity and altered immunopathology. Here, we discuss the nature of T‐cell cross‐reactivity and describe matrices of epitopes from different viruses eliciting cross‐reactive CD8+ T‐cell responses. We examine the parameters of heterologous immunity mediated by these cross‐reactive T cells during viral infections in mice and humans. We show that heterologous immunity can disrupt T‐cell memory pools, alter the complexity of the T‐cell repertoire, change patterns of T‐cell immunodominance, lead to the selection of viral epitope‐escape variants, alter the pathogenesis of viral infections, and, by virtue of the private specificity of T‐cell repertoires within individuals, contribute to dramatic variations in viral disease. We propose that heterologous immunity is an important factor in resistance to and variations of human viral infections and that issues of heterologous immunity should be considered in the design of vaccines.

Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity.

Summary:  The main functions of memory T cells are to provide protection upon re‐exposure to a pathogen and to prevent the re‐emergence of low‐grade persistent pathogens. Memory T cells achieve these functions through their high frequency and elevated activation state, which lead to rapid responses upon antigenic challenge. The significance and characteristics of memory CD8+ T cells in viral infections have been studied extensively. In many of these studies of T‐cell memory, experimental viral immunologists go to great lengths to assure that their animal colonies are free of endogenous pathogens in order to design reproducible experiments. These experimental results are then thought to provide the basis for our understanding of human immune responses to viruses. Although these findings can be enlightening, humans are not immunologically naïve, and they often have memory T‐cell populations that can cross‐react with and respond to a new infectious agent or cross‐react with allo‐antigens and influence the success of tissue transplantation. These cross‐reactive T cells can become activated and modulate the immune response and outcome of subsequent heterologous infections, a phenomenon we have termed heterologous immunity. These large memory populations are also accommodated into a finite immune system, requiring that the host makes room for each new population of memory cell. It appears that memory cells are part of a continually evolving interactive network, where with each new infection there is an alteration in the frequencies, distributions, and activities of memory cells generated in response to previous infections and allo‐antigens.

Immunopathology in RSV Infection Is Mediated by a Discrete Oligoclonal Subset of Antigen-Specific CD4+ T Cells

Vaccination with the respiratory syncytial virus (RSV) attachment (G) protein results in immune-mediated lung injury after natural RSV infection with pathogenic features characteristic of an exaggerated Th2 response. Here we demonstrate that approximately half of the CD4(+) T cells infiltrating the lungs of G-primed mice utilize a single V beta gene (V beta 14) with remarkably limited CDR3 diversity. Furthermore, elimination of these V beta 14-bearing CD4(+) T cells in vivo abolishes the type 2-like pulmonary injury. These results suggest that a novel subset of CD4(+) T cells may be crucial in the development of pathology during human RSV infection and that genetic or environmental factors prior to or at the time of G antigen exposure may affect the commitment of this discrete antigen-specific T cell subset to Th2 differentiation.