Little is currently understood about the consequences of chronic parasitic infection for the fate of memory CD4 + T cells that recognize heterologous antigens, e.g. resulting from prior infections or vaccination. Here, we address how Leishmania donovani infection affected the fate of non-cross-reactive (OVA)-specific memory CD4 + T cells. DO11 cells were adoptively transferred into naive recipient mice, which were then immunized to generate memory DO11 cells. After 6 weeks, mice were infected with L. donovani and the fate of DO11 cells was determined. L. donovani infection stimulated an approximately threefold expansion in the total number of CD4 + T cells and DO11 cells, compared to that observed in uninfected mice. DO11 T cells were more actively dividing in infected mice, as judged by 5-bromo-2 0 deoxyuridine labeling, whereas their rate of apoptosis in control and infected mice was identical. Both CD45RB hi CD44 lo naive T cells and to a greater extent CD45RB lo CD44 hi memory DO11 cells increased in number in the spleens of infected mice, whereas no changes occurred to DO11 cell number or phenotype in the draining lymph nodes. These data indicate that heterologous CD4 + T cells may actively divide during chronic infectious diseases, with important implications for how chronic infection may impact on heterologous immunity.
IntroductionThe generation of memory T cells with enhanced capacity to respond to subsequent antigen exposure is a fundamental tenet of the acquired immune response, underlying host protection associated with cure from primary infection or resulting from vaccination [1]. Nevertheless, the requirements for the maintenance of immunological memory, notably within the CD4 + T cell compartment, remain to be fully elucidated. Of particular scientific as well as practical relevance is the requirement for the maintenance of a source of cognate antigen in the long-term survival of memory T cells. While it has been established that CD8 + T cell memory may be maintained in the complete absence of antigen [2,3], fewer studies have addressed the need for cognate antigen in the maintenance of CD4 + T cell memory. CD4 + memory T cells have been shown to survive long term in the complete absence of antigen [4] or the ability to present it via MHC II [5,6], at least under conditions where competition from other T cells was minimal. 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 infectio...