Immune Elimination ofLeishmania majorin Mice: Implications for Immune Memory, Vaccination, and Reactivation Disease

Abstract

Infection of susceptible BALB/c mice with a large, moderate, or low number of Leishmania major parasites respectively results in progressive disease, the formation of substantial but stable lesions, denoted as borderline disease, and the absence of a visible lesion. Infection with a low number of parasites results over the long term in either subclinical infections or an asymptomatic state. Subclinical mice produce a predominant Th1 response and are resistant to challenge, in contrast to their asymptomatic counterparts. Statistical and other evidence suggest that the asymptomatic state can arise from a subclinical state following parasite clearance, with consequent loss of resistance. Cell transfer studies demonstrate unequivocally that immune cells from subclinical mice can protect naive mice against a pathogenic challenge and can clear the parasite, leaving the mice susceptible to a rechallenge infection. This susceptibility is associated with the disappearance of both parasite-specific effector and memory T cells from secondary lymphoid organs. These findings have implications for vaccination, maintenance of memory, and prevention of reactivation disease.

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

“…However, in contrast to the resistance obtained by low-dose virulent L. major infection of BALB/c mice (6,28,29), no DTH was observed following challenge of lpg2 Ϫ mutant-infected mice, strongly suggesting that distinct mechanisms operate to maintain immunity in low-dose-and lpg2-induced resistance. Moreover, the dose of lpg2 Ϫ parasites used in these experiments would be expected to induce an IL-4 response in BALB/mice, which was not the case.…”

Persistence and Function of Central and Effector Memory CD4+ T Cells following Infection with a Gastrointestinal Helminth

“…Previous studies of CD4 ϩ and CD8 ϩ T cell memory following infection with L. major, Listeria monocytogenes, or lymphocytic choriomeningitis virus have suggested that IFN-␥-producing T EFF or T EM require persistent infection to be sustained, whereas T CM can persist in the absence of chronic infection (18,20,30,31). In contrast, the majority of virus-specific memory CD4 ϩ T cells that are maintained in sites draining the lung in the absence of Sendai virus infection have an activated phenotype (CD44 high , CD62L low ) and rapidly express IFN-␥, characteristics of T EM (21,22).…”

“…In contrast, CD4 ϩ T EFF or T EM confer more rapid protective immunity to L. major infection than T CM (20,30,31). To determine whether the CD4 ϩ T CM or T EM populations-defined by expression of CD62L-that develop following Trichuris infection differed in their ability to mediate protective immunity, purified cells from wild-type immune donors were separated into CD62L high and CD62L low fractions, labeled with CFSE, and transferred into naive congenic recipients that were subsequently infected with Trichuris.…”

Site-Dependent Recruitment of Inflammatory Cells Determines the Effective Dose of Leishmania major

“…Here we demonstrate that even before different antigen-presenting cells begin to prime adaptive immunity, the site of inoculation immediately influences the effective dose of L. major parasites that establishes infection. The parasite dose has far-reaching implications for Leishmania infections, including the nature of the adaptive immune response, and is likely one of the most important variables in determining the kinetics and outcome of infection (6,36,(44)(45)(46)(47)(48)). Our observations demonstrate that the number of parasites that establishes infection must be considered in interpreting the influence of the site of infection, as suggested previously (6).…”