Long-lasting Immunological Memory Research Articles

Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity.

Vaccine efficacy is determined largely by cellular and humoral immunity as well as long-lasting immunological memory. IL-2 and IL-15 were evaluated in vaccinia vectors expressing HIV gp160 for the establishment of an effective vaccine strategy. Both IL-2 and IL-15 in the vaccinia vector induced strong and long-lasting antibody-mediated immunity as well as a short-term cytotoxic T cell response against HIV gp120. In addition, IL-15 also supported robust CD8+ T cell-mediated long-term immunity, whereas the CD8+ T cell-mediated immunity induced by IL-2 was short-lived. Moreover, we found that the cytokine milieu at the time of priming had surprisingly persistent effects on the character of the memory CD8 T cells long afterward with respect to their fate, functional activities, cytokine receptor expression, and antigen-independent proliferation.

Vaccination against the major infectious diseases

The reputation of vaccination rests on a 200-year-old history of success against major infectious diseases. That success has led to the doctrine of ‘for each disease, a vaccine’. Although some diseases have proved frustrating, this doctrine carries considerable truth. However, when one reviews the vaccines now available it is apparent that most successes have been obtained when the microbe has a bacteremic or viremic phase during which it is susceptible to the action of neutralizing antibodies, and before replication in the particular organ to which it is tropic. Poliomyelitis and infections by capsulated bacteria are examples where vaccination has worked efficiently. However, some success has also been achieved against agents replicating on respiratory or gastrointestinal mucosae. Influenza, pertussis and rotavirus vaccines are examples of such agents, against which it has been possible to induce immune responses acting locally as well as systemically. In addition, when bacteria produce disease through exotoxins, purification and chemical or genetic inactivation of those toxins has yielded highly efficacious vaccines. Control of intracellular pathogens has not been achieved, except partly with the BCG vaccine against tuberculosis, and modern efforts are directed towards pathogens against which cellular immune responses are critical. In general, two achievements have been crucial to the success of vaccines: the induction of long-lasting immunological memory in individuals and the stimulation of a herd immunity that enhances control of infectious diseases in populations.

Self-defense: the fruit fly style.

The immune system of higher vertebrates consists of innate and adaptive components that differ mainly by the mechanisms of pathogen recognition: the innate immune system uses germ-line encoded receptors to recognize conserved molecular constituents of infectious microorganisms, whereas adaptive immunity is mediated by highly specific antigen receptors that are generated by gene-rearrangement processes during the ontogeny of each individual organism and are distributed clonally on the two types of lymphocytes—T cells and B cells (1, 2). As antigen receptors are generated by random processes, they can potentially be specific for any antigen. One of the essential functions of the innate immune system is believed to be instructing lymphocytes about the nature of the antigen for which they happen to be specific. This choice of effector function is essential for the effective operation of the adaptive immune response, as lymphocytes generate their antigen receptors randomly, and thus can be specific for many different types of antigen. The innate immune system sorts out whether the antigen is derived from a pathogen, in which case a response is induced and used for host defense. In cases in which the antigen is produced by the host organism, an immune response would be harmful to the host and therefore is not induced. Because the receptors of innate immunity recognize molecular structures produced only by microbes and not by the host organism, they activate signaling pathways that inform the lymphocytes of the microbial origin of the antigen. When this activation happens, lymphocytes specific for the antigen in question start to proliferate and differentiate into one of the several possible types of lymphoid effector cells. This differentiation process, however, is not pre-programmed in lymphocytes. Rather, it also depends on signals generated by the innate immune system (3–5). The best known signals of this kind are represented by a subgroup of cytokines that are believed to convey information concerning the type of pathogen invading the host organism. These cytokines thus direct differentiation of the lymphocytes into effector cells, that, in turn, activate the appropriate destructive mechanism to ultimately eliminate or neutralize the microbial pathogens (6). Additionally, some of the lymphocytes derived from the same clone differentiate into long-lived cells that retain the imprint of the instructions they received on initial infection. These cells can rapidly produce the same effector responses to all subsequent infections with the same pathogen. This sophisticated mechanism provides for long-lasting immunological memory to pathogens encountered during the lifetime of the host organism.

Intracellular growth of Listeria monocytogenes as a prerequisite for in vivo induction of T cell-mediated immunity.

The in vivo induction of T cell-mediated immunity was studied by infecting mice with two genetically closely related mutants from Listeria monocytogenes, differing only with respect to the secretion of an active SH-dependent hemolysin. It is shown that even minute doses of hemolytic bacteria capable of growing in host tissues easily induced the expression of T cell-mediated immunity, as estimated by the level of delayed sensitivity, adoptive protection and long-lasting immunological memory. On the contrary, nonhemolytic bacteria unable to multiply in host tissues totally failed to initiate the expression of T cell-mediated immunity in vivo. This failure was even observed when mice were repeatedly infected by high doses of nonhemolytic bacteria, allowing to maintain a significant amount of viable bacteria for several days in host tissues. These results mean that the presence of viable bacteria at a significant level in the host is not sufficient per se to induce detectable T cell clonal expansion in the in vivo setting, implying that the process of bacterial growth inside macrophages is required to initiate in vivo the expression of T cell-mediated immunity.