Phenotypic Definition of Effector and Memory T-Lymphocyte Subsets in Mice Chronically Infected withMycobacterium tuberculosis

Abstract

The bacterium Mycobacterium tuberculosis remains one of the world's most successful pathogens, a situation that is aggravated by the fact that the existing vaccine, Mycobacterium bovis BCG, is not effective in adults. As with any vaccine, the purpose of giving BCG vaccination is to establish a long-lived state of memory immunity, but whether this is successfully completely established is still unclear. It is generally accepted that memory T cells can be divided into central and effector memory populations by function and by phenotype; however, the majority of data supporting this division have been generated using transgenic mouse models or mice that have recovered from acute viral infections. Tuberculosis, on the other hand, represents a persistent, chronic state of immunity in which the presence of memory T cells is far less well defined. We show here that mice vaccinated with BCG or chronically infected with M. tuberculosis establish antigen-specific populations of cells within the lungs that predominantly express a cellular phenotype consistent with their being effector or effector memory cells. In contrast, cells with a central memory phenotype exist in much lower numbers in the lungs but can be found in significantly larger numbers in the spleen, where they may represent a potential reservoir. These data suggest that the effector-to-central-memory T-cell transition may well be minimal in these persisting mycobacterial infections, and they support a novel hypothesis that this may explain the fundamental basis of the failure of the BCG vaccine in humans.

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

“…It has previously been shown that in mice vaccinated with BCG, the T cells are primarily effector or effector-memory T cells 6 mo after vaccination (32). In contrast we have shown that 1 y after vaccination with a fusion protein (H1) formulated in the same adjuvant used in this study, the T cells are primarily central memory T cells (33).…”

The History of Tuberculosis and Bacillus Calmette–Guérin Vaccine in Iran

“…Meta-analysis of 14 prospective and 12 case-control studies revealed that the protective efficacy of BCG against pulmonary disease varies significantly with geographical latitude (14). This vaccine also appears to generate CD4+ central memory T cells rather poorly, potentially compromising control of subsequent TB infection (19,20). Another factor that may underlie BCG failure is the unusually high concentrations of IL-4 that have been found in patients from developing countries (21,22).…”

Control of Chronic Mycobacterium tuberculosis Infection by CD4 KLRG1− IL-2–Secreting Central Memory Cells

“…It has previously been reported that BCG is unable to maintain a large population of high-quality memory cells (10,36,54). BCG-promoted responses are (like the real TB infection) dominated by effector-like T cell subsets secreting IFN-g and/or TNF-a (41,54,55), and the numbers of IL-2 + T cells are much lower than after a H1/CAF01 subunit vaccination (36). The recent identification of BCG-specific CD4 T cells with a central memory phenotype (based on CCR7 expression) in a longitudinal study of infants (29) seems at odds with the observations in the mouse model and led Soares et al (29) to suggest that BCG might be cleared more rapidly in humans than in mice.…”