A holistic view of memory generation: where do T cells reside?

Abstract

The generation of memory cells is the explanation for the protection of an individual from a secondary infection with the same agent. The existence and function of memory cells is well established, but their preferred site of residence in the body is still unclear. Likewise, it is controversial whether naive T cells reside exclusively in secondary lymphoid tissues, or whether they are also present in other parts of the body. To settle these issues unequivocally, Reinhardt and colleagues 1xVisualizing the generation of memory CD4 T cells in the whole body. Reinhardt, R.L. et al. Nature. 2001; 410: 101–105Crossref | PubMed | Scopus (745)See all References1 chose an approach that is fascinating, in both the beauty and the clarity of its results.To follow the fate of antigen-specific T cells in vivo, the authors injected naive T-cell receptor (TCR)-transgenic T cells, which recognize a peptide of chicken ovalbumin (OVA) in the context of MHC class II molecules, into naive mice. To localize the T cells in situ, they prepared whole-body histologies of the mice. The transferred T cells could be tracked either via allelic differences in Thy1 expression or via an anti-TCR clonotypic antibody. In the absence of specific peptide (OVA), the inoculum of naive T cells resided predominantly in the spleen, demonstrating that naive T cells do indeed preferentially accumulate in secondary lymphoid tissues. In vivo priming of naive T cells, by intravenous injection of OVA peptide without adjuvant, led to their transient expansion within secondary lymphoid organs, followed by a gradual accumulation in peripheral tissues, especially the gut, and an almost complete loss from spleen, lymph nodes and thymus within three days. Primed T cells in peripheral organs were also lost over a period of two weeks, resulting in the absence of detectable memory cells in these hosts. However, when the OVA peptide was administered together with lipopolysaccharide (LPS), expansion of T cells was much more dramatic and the cells were maintained in the periphery, especially in the gut, for >60 days. Thus, the presence of a microbial adjuvant was required to generate a long-lasting memory-T-cell pool.When the authors checked the lymphokine production of in vivo activated cells from different tissues, they found a high percentage of interferon γ (IFN-γ)-producing cells in the lung, whereas few IFN-γ-producing cells were found in the spleen and almost none in lymph nodes. By contrast, antigen-specific cells producing interleukin 2 (IL-2) were most prominent in lymph nodes and spleen, whereas in the lung only a fraction of the OVA peptide-responsive cells produced IL-2. Thus, IFN-γ-producing effector T cells reside primarily in peripheral tissues, but a pool of IL-2-producing memory cells remains in central lymphoid organs. These results might not have been entirely unexpected, but this study now provides visual evidence for a significant compartmentalization of diverse T-cell subsets. Thus, analyzing T-cell responses in isolated lymphoid organs might not be representative of the T-cell response in the entire organism.The paper also illustrates the enormous dynamics of in vivo memory responses. Only two hours after OVA infusion, ≈30% of the OVA-specific T cells in the lung were found to produce IFN-γ and 50% of these cells in the lymph nodes produced IL-2. After 24 hours, >70% of all antigen-specific cells in the spleen had upregulated the activation marker CD25. These results also demonstrate the importance of adjuvant for effective vaccination, given the profound influence of a microbial stimulus on the extent, duration and localization of a specific T-cell response.