Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections.

Abstract

Experimental analyses of the acute cytotoxic T lymphocyte (CTL) response to viruses have focused on studying these infections in immunologically naive hosts. In the natural environment, however, viral CTL responses occur in hosts that are already immune to other infectious agents. To address which factors contribute to the maintenance and waning of immunological memory, the following study examined the frequencies of virus-specific CTL precursor cells (pCTL) not only using the usual experimental paradigm where mice undergo acute infections with a single virus, and in mice immune to a single virus, but also in immune mice after challenge with various heterologous viruses. As determined by limiting dilution assays, the pCTL frequency (p/f) per CD8+ T cell specific for lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), or vaccinia virus (VV) increased during the acute infections, peaking at days 7-8 with frequencies as high as 1/27-1/74. Acute viral infections such as these elicit major expansions in the CD8+ T cell number, which has been reported to undergo apoptosis and decline after most of the viral antigen has been cleared. Although the decline in the total number of virus-specific pCTL after their peak in the acute infection was substantial, for all three viruses the virus-specific p/f per CD8+ T cell decreased only two- to fourfold and remained at these high levels with little fluctuation for well over a year. The ratios of the three immunodominant peptide-specific to total LCMV-specific clones remained unchanged between days 7 and 8 of acute infection and long-term memory, suggesting that the apoptotic events did not discriminate on the basis of T cell receptor specificity, but instead nonspecifically eliminated a large proportion of the activated T cells. However, when one to five heterologous viruses (LCMV, PV, VV, murine cytomegalovirus, and vesicular stomatitis virus) were sequentially introduced into this otherwise stable memory pool, the stability of the memory pool was disrupted. With each successive infection, after the immune system had returned to homeostasis, the memory p/f specific to viruses from earlier infections declined. Reductions in memory p/f were observed in all tested immunological compartments (spleen, peripheral blood, lymph nodes, and peritoneal cavity), and on average in the spleen revealed a 3 +/- 0.4-fold decrease in p/f after one additional viral infection and an 8.4 +/- 3-fold decrease after two additional viral infections. Thus, subsequent challenges with heterologous antigens, which themselves induce memory CTL, may contribute to the waning of CTL memory pool to earlier viruses as the immune system accommodates ever-increasing numbers of new memory cells within a limited lymphoid population. This demonstrates that virus infections do not occur in immunological isolation, and that CD8+ T cell responses are continually being modulated by other infectious agents.

The fate of heterologous CD4+ T cells during Leishmania donovani infection

“…Studies on the dynamics of T cell responses during infectious disease have been largely limited to studies of acute viral and bacterial infections, and have led to the conclusion that the expansion of immunodominant clones leads to the attrition of pre-existing memory T cells [9,26,27]. In this study, we have examined the dynamics of CD4 + T cells during chronic infection with L. donovani and addressed how this infection impacts on the survival and proliferative status of non-crossreactive OVA-specific TCR transgenic CD4 + T cells.…”

“…The generalization of these observations has, however, yet to be demonstrated, and most models of clonal attrition involve viral or bacterial infections with rapid and extensive expansion of highly immunodominant T cell clones [9,10]. To date, the relative importance of these issues in the context of chronic parasitic infections has been largely ignored.…”

“…However, such situations may have limited physiological importance. In a contrasting study, intermittent stimulation by persisting antigen was shown to be necessary for CD4 + memory T cell survival [7], although again competition from other T cells was not taken into account.In addition to the possible role of antigen in maintaining CD4 + T cell memory, a number of studies have suggested that the memory T cell compartment itself is of finite size, opening the way for inter-clonal competition for space within this compartment [2,8].The generalization of these observations has, however, yet to be demonstrated, and most models of clonal attrition involve viral or bacterial infections with rapid and extensive expansion of highly immunodominant T cell clones [9,10]. To date, the relative importance of these issues in the context of chronic parasitic infections has been largely ignored.…”

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

“…Homeostatic regulation of the size of lymph nodes and spleen led researchers to believe an upper boundary exists for the total number of memory T cells. In mice, studies have shown that new memory T cells generated during heterologous infections lead to a decrease in memory CD8+ T cells specific for a prior infection, raising the concern that periodic herpesvirus reactivation and expansion of memory CD8 T cells over time would lead to significant memory T cell attrition and impaired immune responses (Selin et al 1996(Selin et al , 1999Liu et al 2003). However, recent evidence suggests this is not what occurs in humans.…”

A stochastic model of cytotoxic T cell responses

“…New memory cells from heterologous infections can displace the memory cells from responses to prior infections (Selin et al, 1996;McNally et al, 2001). In the absence of immune system challenges, memory cells turn over slowly (Dutton et al, 1998;Murali-Krishna et al, 1999).…”