CD4+ Th Cell Specificity and Memory Responses to Variable and Conserved Variant Surface Glycoprotein Sequences in African Trypanosomiasis

Trypanosoma brucei rhodesiense is an extracellular protozoan parasite that causes African sleeping sickness. Transmitted by the tsetse fly, T.b. rhodesiense is endemic in sub-Saharan Africa, affects thousands each year, and causes an inevitably fatal infection. Treatments are not always effective, and some are highly toxic. A vaccine has remained elusive because of the parasite's ability to vary the composition of its variant surface glycoprotein (VSG) coat by switching expression of the gene that encodes it. The adaptive immune response to VSG encompasses both B cells and CD4+ Th cells, but little is known about resulting immunological memory. Because an effective CD4+ Th cell response determines relative host resistance, we explored the nature of CD4+ Th cell memory in T.b. rhodesiense infection.;Previous studies have shown that T.b. rhodesiense infection results in a polarized Th1 response characterized by the production of IFN-gamma by CD4+ Th cells. We show that CD4+ Th cells quickly transition to a memory phenotype after infection, but they are soon unable to respond to ex-vivo stimulation. However, both CD4+ Th cell and antigen-presenting cell function are fully restored in drug-treated mice, implying that memory responses are impaired by chronic infection. Further, we show that after a prolonged rest period, CD4+ Th cells from drug-treated mice that are adoptively transferred readily proliferate upon infection of recipients, which supports that these are truly memory cells and not effectors.;Although the N-terminal region of the VSG molecule changes with each VSG gene conversion event, the VSG C-terminus is relatively conserved among parasite isolates of the same VSG C-terminal Type. CD4+ Th cell responses to the VSG C-terminal region have never been detected, but we hypothesized that we could enhance recognition of a VSG C-terminal peptide through a prime-boost strategy. We see an increased response to the VSG C-terminal peptide in immunized mice, as well as enhanced survival. Thus, the experiments presented are the first to show that functional memory CD4+ Th cells are generated to parasite VSG, and we maintain that enhancing CD4+ Th cell responses to conserved VSG residues holds the potential for conferring cross-protection against newly-arising variants.