Effector CD4⁺ and CD8⁺ T‐cell mechanisms in the control of respiratory virus infections

Abstract

The rules for T-cell-mediated control of viruses that infect via the respiratory mucosae show both common themes and differences, depending on the nature of the pathogen. Virus-specific CD8+ cytotoxic T lymphocytes (CTLs) are the key effectors of virus clearance in mice infected with both negative strand RNA viruses (influenza and Sendai) and a DNA virus, the murine gamma-herpesvirus-68 (MHV-68). Recently completed experiments establish that these activated CD8+ T cells indeed operate primarily via contact-dependent lysis. Perforin-mediated cytotoxicity seems to be the preferred mode, though a Fas-based mechanism can apparently serve as an alternative mechanism. Immune CD4+ T cells functioning in the absence of the CD8+ subset cannot eliminate MHV-68 from lung epithelial cells, are somewhat less efficient than the CD8+ CTLs at clearing the RNA viruses, and are generally ineffectual in mice that lack B lymphocytes. Though cytokine secretion by CD4+ and CD8+ T cells in the virus-infected lung may promote both T-cell extravasation and macrophage activation, such processes are not alone sufficient to deal consistently with any of these infections. However, CD4+ T help is mandatory for an effective B-cell response, and can operate to promote the clonal expansion of virus-specific CD8+ T cells in the lymph nodes and spleen. Furthermore, a concurrent CD4+ T-cell response seems to be essential for maintaining continued CD8+ T-cell surveillance and effector capacity through the persistent, latent phase of MHV-68 infection in B cells. Thus, the evidence to date supports a very traditional view; CD8+ T cells function mainly as killers and the CD4+ T cells as helpers in these respiratory virus infections.

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

“…If the viral load is dependent primarily on the rate of virus production, but not spread, then it becomes intuitive that the elimination of the virus "factories" by CTLs has the largest impact on reducing virus titers. This prediction is borne out by both the biological observations (2,11,12,52) and the model fitting of the adaptive phase to the experimental data. In the same way, the effect of antibody-mediated inhibition of virus spread by IgG would have relatively little influence since it effectively diminishes infectivity.…”

Uneven distribution of MHC class II epitopes within the influenza virus

“…The best understood system is the class I-restricted CD8 + T cell response to influenza virus infection in inbred mice. For example, 16 H-2K b and H-2D b -restricted epitopes have been identified in C57BL/6 mice following influenza virus infection and these epitopes have provided insight into the breadth of the T cell response and patterns of immunodominance [3][4][5][6][7][8]. In addition, these epitopes have provided a basis for mechanistic and vaccine studies, and reagent development, including MHC-peptide tetramers.…”

Heterogeneity of Effector Phenotype for Acute Phase and Memory Influenza A Virus-Specific CTL

“…Activated CD8 ϩ CTLs play a major part in the acute control of most virus infections (10). Prominent in the CTL cytoplasm are secretory granules that contain a spectrum of cytotoxic molecules including perforin (Pfp) 4 and a group of serine proteases (11) called granzymes (granule enzymes; Gzm).…”