Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells.

Abstract

SummaryA unique experimental model has been developed for dissecting the integrity of CD8 + T cellmediated immunity to a persistent gammaherpesvirus under conditions of CD4 + T cell deficiency. Respiratory challenge of major histocompatibility complex class II -/-and +/+ C57BL/6J mice with the murine gammaherpesvirus 68 (MHV-68) leads to productive infection of both lung and adrenal epithelial cells. Virus titers peak within 5-10 d, and are no longer detected after day 15. Persistent, latent infection is established concurrently in splenic and lymph node B cells, with higher numbers of MHV-68 § lymphocytes being found in all lymphoid sites analyzed from the +/+ mice concurrent with the massive, but transient splenomegaly that occurred only in this group. From day 17, however, the numbers of infected B lymphocytes were consistently higher in the -/-group, while the frequency of this population diminished progressively in the +/+ controls. Infectious MHV-68 was again detected in the respiratory tract and the adrenals of the -/-(but not the +/+) mice from day 22 after infection. The titers in these sites rose progressively, with the majority of the -/-mice dying between days 120 and 133. Even so, some CD8 + effectors were still functioning as late as 100 d after infection. Depletion of CD8 + T cells at this stage led to higher virus titers in the -/-lung, and to the development of wasting in some of the -/-mice. Elimination of the CD8 + T cells from the +/+ group (day 80) increased the numbers ofMHV-68 + cells in the spleen, but did not reactivate the infection in the respiratory tract. The results are consistent with the interpretation that CD8 + T cell-mediated control of this persistent gammaherpesvirus is progressively lost in the absence of the CD4 + T cell subset. This parallels what may be happening in AIDS patients who develop Kaposi's sarcoma and various Epstein Barr virus-associated disease processes.

Clonal Exhaustion as a Result of Immune Deviation

“…The number of CD8 + T cells drops, recrudescence of viraemia occurs, and the system approaches the exhausted state, albeit at a long time scale. This is in excellent agreement with the data reported previously (Cardin et al, 1996;Thomsen et al, 1996;Planz et al, 1997). Our results suggest that the persistence of virus at higher levels plays a crucial role in the exhaustion of some partially immunodeficient hosts.…”

“…For the sake of simplicity, we do not include the dynamics of CD4 + T lymphocytes in our model. However, the late exhaustion depends heavily on CD4 + T cell help, probably via partial control of the virus (Battegay et al, 1994;Matloubian et al, 1994;Cardin et al, 1996;Thomsen et al, 1996). The implications of this for late exhaustion will be discussed in Section 3.3.…”

“…Partially immunodeficient hosts (e.g., MHC Class II and B cell deficient, or CD4 + T cell depleted hosts) are more vulnerable to the induction of exhaustion, i.e., the exhaustion can be induced with milder LCMV strains even at a low inoculum dose (Matloubian et al, 1994;Brundler et al, 1996;Cardin et al, 1996;Thomsen et al, 1996;Planz et al, 1997). The influenza virus infections in CD4 + T cell depleted hosts show a similar pattern (D. Wodarz, personal communication).…”

“…Overwhelming infection of immunocompetent naive hosts induces exhaustion within 2 weeks (i.e., early exhaustion) (Moskophidis et al, 1993a,b;Tishon et al, 1993). Partially immunodeficient mice (e.g., MHC Class II and IgM knockout, CD4 + T cell depleted) immunized with optimal dose and mild strains of LCMV become exhausted 40-200 days after immunization (i.e., late exhaustion) (Matloubian et al, 1994;Cardin et al, 1996;Thomsen et al, 1996;Planz et al, 1997). Congenital and neonatal infections usually become persistent, irrespective of the virus strain and inoculum size used.…”

Immune surveillance of intracellular pathogens via autophagy

“…This suggests that MHC class II molecules on inflamed tissues might display primarily endogenous ligands for immune surveillance by CD4 þ T cells. The induction of CD4 þ T cells alongside with CD8 þ T cells is an important prerequisite for an effective adaptive immune response, since the development [77][78][79] and maintenance [80][81][82][83][84] of CD8 þ memory T cells is dependent on help from CD4 þ T cells. Additionally, CD4 þ T cells can have direct Figure 2 Autophagy as a novel pathway for endogenous MHC class II presentation.…”