T Memory Cells: Quality not Quantity Dispatch

Exposure to infectious microorganisms generally leads to a powerful immune response by specific T and B cells [1,2]. Contact with the pathogen in the lymph nodes and spleen causes specifically reactive T and B cells to proliferate extensively and differentiate into effector cells. These cells then home to the sites of infection and, via a combination of cellular and humoral (antibody-mediated) immunity, induce rapid destruction of the pathogen. Being now redundant, most effector T and B cells are destroyed. However, some of these cells survive and differentiate into longlived memory cells (Figure 1). Immunological memory is often lifelong and results in a heightened response to the pathogen upon reinfection [3–6]. Since memory at the T cell level is associated with a marked increase in the frequency of antigen-specific lymphocytes, the simplest explanation for the efficiency of secondary (memory) immune responses is that there are more reactive cells available to attack the pathogen than in the primary response. But is an increase in precursor frequency alone sufficient to account for memory? According to a paper published recently in Science by Lauvau et al. [7], the answer seems to be no. In this paper the authors found that priming mice with either live or heat-killed bacteria led to intense proliferation of antigen-specific T cells followed by survival of a proportion of these cells as memory cells. Surprisingly, when the mice were later injected with live bacteria, protective immunity to the pathogen was seen only after priming with live bacteria. Priming with killed bacteria was conspicuously ineffective. To study the requirements for induced protective immunity, Lauvau et al. [7] examined memory in mice injected intravenously with Listeria monocytogenes, a Gram-positive facultative intracellular bacterium (Table 1); immunity to this bacterium is known to be controlled largely by CD8+ T cells. To follow the response of antigen-specific CD8+ cells to the bacterial antigens, the authors utilized the finding that CD8+ cells react to antigenic peptides bound to class I major histocompatibility complex (MHC) molecules and that peptide-specific CD8+ cells can be detected via binding of soluble MHC class I tetramers plus specific peptide [6]. As expected, priming mice with live bacteria led to marked clonal expansion of specific CD8+ cells in the primary response and even greater expansion in the secondary response. Based on T cell binding of three different peptide–tetramer complexes, the precursor frequency of CD8+ cells for the bacterial antigens rose from undetectable levels before priming to 2–3% of CD8+ cells at the height of the primary response (day 7) and then to about 25% during the secondary response (day 5). Testing the mice 21 days after initial injection of live bacteria showed strong protective immunity. Thus, when the mice received a second intravenous injection of live bacteria, counts of viable bacteria in the spleen measured 3 days later were far lower than were found at this time in the primary response. These results refer to priming with live bacteria. When mice were primed with heat-killed bacteria, clonal expansion and persistence of specific CD8+ cells was as high as for priming with live bacteria. Thus, when mice were primed with killed bacteria and then challenged with live bacteria 21 days later, 27% of CD8+ cells in the spleen were antigen-specific on day 5 after challenge (compared with 24% for mice primed – and challenged – with live virus). Despite this Current Biology, Vol. 12, R174–R176, March 5, 2002, ©2002 Elsevier Science Ltd. All rights reserved. PII S0960-9822(02)735-2