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

Abstract

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...

Bystander stimulation of activated CD4+ T cells of unrelated specificity following a booster vaccination with tetanus toxoid

“…Previous mouse studies reported bystander activity in the presence of a chronic parasitic infection (L. donovani), associated with a strong inflammatory response [6]. In our case, non-specific stimulation of the activated OT-II cells by a pro-inflammatory environment was unlikely since no adjuvant was used at boosting, and could be excluded by the fact that injection of control protein had no effect.…”

“…Such responses could contribute to the antigen-independent maintenance of T cells at different stages, including memory T cells. Our next goal is to test the effects of bystander stimulation on survival and functionality of transferred memory cells generated in vivo [6] rather than on cells stimulated in vitro, mimicking more closely our observations in human subjects [16]. Whatever the stage of the responding T cells, a balance between maintenance of memory and a potentially pathological effect of cytokine-activated cells must be struck.…”

“…However, it has been shown that chronic parasitic infection (Leishmania donovani), associated with a strong inflammatory response, induces expansion of heterologous CD4 1 memory T cells [6]. In a model of herpetic stromal keratitis, a chronic inflammatory reaction in the corneal stroma, which follows ocular infection with herpes simplex virus, a nonantigen-specific bystander activation of CD4 1 T cells appears to account for the immunopathological lesions [7,8].…”

Vaccination of human subjects expands both specific and bystander memory T cells but antibody production remains vaccine specific

“…31 A close parallel to our observations in human subjects was described recently in a mouse model where infection with Leishmania donovani led to expansion of adoptively transferred transgenic ovalbumin (OVA)-specific memory CD4 ϩ T cells. 32 In this case, OVA antigen was required, possibly to maintain the transferred cells, whereas in our case it is unlikely, but not impossible, that PPD or C albicans antigens or cross-reactive antigens persist in vivo. While definitive data on generation and survival of T mem cells can be obtained from transgenic and knockout mice, it is difficult to mimic the situation in human subjects who have a normal T mem -cell repertoire under continuous exposure to environmental antigens.…”

Interleukin-10 and the pathogenesis of human visceral leishmaniasis

“…This might in part be owing to sequestration of CD45RO + CD4 T cells in lesional tissue. In mice, both heterologous T cells and those with specificity for the parasite accumulate in the VL spleen [57]. The specificity of splenic T cells that accumulate in the human VL spleen has not been addressed to date.…”