Immunological memory≠protective immunity

So-called ‘immunological memory' is, in my view, a typical example where a field of enquiry, i.e. to understand long-term protection to survive reexposure to infection, has been overtaken by ‘l'art pour l'art' of ‘basic immunology'. The aim of this critical review is to point out some key differences between academic text book-defined immunological memory and protective immunity as viewed from a co-evolutionary point of view, both from the host and the infectious agents. A key conclusion is that ‘immunological memory' of course exists, but only in particular experimental laboratory models measuring ‘quicker and better' responses after an earlier immunization. These often do correlate with, but are not the key mechanisms of, protection. Protection depends on pre-existing neutralizing antibodies or pre-activated T cells at the time of infection—as documented by the importance of maternal antibodies around birth for survival of the offspring. Importantly, both high levels of antibodies and of activated T cells are antigen driven. This conclusion has serious implications for our thinking about vaccines and maintaining a level of protection in the population to deal with old and new infectious disease

Protective Immunity Does Not Correlate with the Hierarchy of Virus-specific Cytotoxic T Cell Responses to Naturally Processed Peptides

Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) stimulates major histocompatibility complex class I–restricted cytotoxic T cells (CTLs), which normally resolve the infection. Three peptide epitopes derived from LCMV have been shown to bind the mouse class I molecule H-2 Db and to stimulate CTL responses in LCMV-infected mice. This report describes the identity and abundance of each CTL epitope after their elution from LCMV-infected cells. Based on this information, peptide abundance was found to correlate with the magnitude of each CTL response generated after infection with LCMV. Subsequent experiments, performed to determine the antiviral capacity of each CTL specificity, indicate that the quantitative hierarchy of CTL activity does not correlate with the ability to protect against LCMV infection. This report, therefore, indicates that immunodominant epitopes should be defined, not only by the strength of the CTL response that they stimulate, but also by the ability of the CTLs to protect against infection

Enhanced positive selection of a transgenic TCR by a restriction element that does not permit negative selection

Very little is known about the conformational properties of the MHC molecules that are able to signal positive selection of a given TCR. To try to understand these parameters and to determine whether these requirements are shared with interactions during negative selection and antigen recognition, we have studied selection and antigen recognition of a transgenic TCR (specific for lymphocytic choriomeningitls virus glycoprotein and H-2Db) in the context of two Db mutants, H-2bm13 and H-2bm14. The data showed that the transgenic TCR was not positively selected by the H-2bm14 haplotype but, interestingly, enhanced positive selection was seen in H-2bm13 mice. The transgenic TCR could not be negatively selected In H-2bm13animals persistently infected with the virus (neonatal virus carrier mice), nor could the transgenic TCR be activated by H-2bm13 infected cells in vivo or in vitro. These experiments show that although a TCR may be selected by a mutant MHC molecule, the corresponding viral antigen cannot be recognized in the context of the mutant MHC molecule, as Judged by both negative selection and T cell reactivity in vivo and in vitro. The ‘enhanced' positive selection occurring in the context of Dbm13 suggests that a different conformation of the MHC molecule is able to select the same TCR and also that various TCR-ligand avidities may permit positive selectio

Neonatal tolerance to Mls-1a determinants: deletion or anergy of Vβ6 + T lymphocytes depending upon MHC compatibility of neonatally injected cells

Recent investigations in mice revealed that natural immunologlcal tolerance to endogenous minor lymphocyte-stimulating locus 1a (MIs-1a antigen correlates primarily with deletion of Mls-1aspeciflc Vβ6+ T lymphocytes In the thymus. Similar mechanisms account for acquired tolerance in some Instancessince the neonatal injection of Mls-1 a-expressing MHC compatible cells in neonatal mice within the first 24 hof life causes clonal deletion of Vβ6+ T cells. Here we demonstrate that Vβ6+ T cells are not deleted In mice neonatally treated with Mls-1a spleen cells expressing allogenelc H-2 molecules. However, when such non-deleted Vβ6+ T cells were tested In vitro, no interleukin 2 (IL-2) secretion or proliferation was observed after Mls-1a stimulation. This non-responsive state could be overcome by addition of exogenous IL-2, consistent with the fact that Vβ6+ cells enlarged and expressed IL-2 receptors upon Mls-1a stimulation. Furthermore, the same neonatally treated mice showed In vitro functional unresponsiveness of cytotoxic T cells but not of IL-2-secreting cells specific for the tolerated allogeneic MHC antigens. Taken together, our data Indicate that neonatal tolerance to Mls-1a can be accomplished by either clonal deletion or clonal anergy, and that it does not necessarily correlate with tolerance to MHC determinant