Trying to See the Forest through the Trees: Deciphering the Nature of Memory Immunity to Mycobacterium tuberculosis

Abstract

The purpose of vaccination against tuberculosis and other diseases is to establish a heightened state of acquired specific resistance in which the memory immune response is capable of mediating an accelerated and magnified expression of protection to the pathogen when this is encountered at a later time. In the earliest studies in mice infected with Mycobacterium tuberculosis, memory immunity and the cells that express this were definable both in terms of kinetics of emergence, and soon thereafter by the levels of expression of markers including CD44, CD62L, and the chemokine receptor CCR7, allowing the identification of effector memory and central memory T cell subsets. Despite these initial advances in knowledge, more recent information has not revealed more clarity, but instead, has created a morass of complications-complications that, if not resolved, could harm correct vaccine design. Here, we discuss two central issues. The first is that we have always assumed that memory is induced in the same way, and consists of the same T cells, regardless of whether that immunity is generated by BCG vaccination, or by exposure to M. tuberculosis followed by effective chemotherapy. This assumption is almost certainly incorrect. Second, a myriad of additional memory subsets have now been described, such as resident, stem cell-like, tissue specific, among others, but as yet we know nothing about the relative importance of each, or whether if a new vaccine needs to induce all of these, or just some, to be fully effective.

Keywords: BCG; Mycobacterium tuberculosis; memory T cell subsets; memory immunity; vaccination.

Figure 1

Possible distribution of key reactive lymphocytes in the bronchial epithelium (first line of defense) and lymph nodes and spleen, in memory immune animals. Transport of bacilli and/or antigen out of the alveolus or swollen interstitium by dendritic cells (DC) will trigger responses by local responses by effector memory T cells (TEM) and resident T cells (TRM), as well as potentially by local mucosal-associated invariant T cells, as well as rapid responses by TEM and central memory T cells (TCM) from the draining lymph nodes and spleen. Whether TSCM act directly or feed the expansion of TCM is as yet unknown.

Figure 2

Our working hypothesis for the distinction between intravascular T cells and other subsets in the lungs. Large activated blast lymphocytes plug the proximal end of the lung blood capillary system, where they are readily stained by anti-CD45 antibody. These cells have to considerably deform before they can be pushed by hydrostatic pressure through the system. It is not clear, however, how long this process takes but it could be several hours. Once they encounter sites of infection, they pass out of the blood capillary and either cross the damaged alveolar epithelium or pass into the swollen interstitium. After encountering infected local macrophages, they release IFNγ, thus becoming negative upon staining for this cytokine. In addition, some express KLRG-1, needed for the cell to bind cadherins in the extracellular matrix, facilitating granuloma formation.