Lymphopenia-Associated CD4+ T Cell-Mediated Colitis Correlates with Homeostatic but Not with Endogenous Proliferation.

Transfer of peripheral T cells into lymphopenic hosts results in a burst-like proliferation, called endogenous proliferation (EP) and an antigen-independent proliferation, called homeostatic proliferation (HP). Formerly both were named lymphopenic or homeostatic proliferation. T cells that undergo either endogenous or homeostatic proliferation acquire an activated phenotype, develop the ability to produce Interferon-gamma (IFN-g) and to lyse target cells specifically, but only homeostatic proliferating T cells acquire a CD44^bright CD62L^bright phenotype.

We developed a murine model to distinguish effects of both types of lymphopenia-associated proliferation. In this model we were able to induce polyclonal populations of syngenic CD4+ or CD8+ peripheral T cells (derived from C57BL/6 mice) to proliferate homeostatically (after transfer into lymphopenic RAG−/− mice) whereas only EP occurred when transferring into mice that inherit only an additional single CD8+ T cell clone (transfer into the non-lymphopenic P14/RAG−/− mice).

CFSE dilution was observed from CD4+ or CD8+ T cells transferred into RAG−/− mice, whereas HP was inhibited when transferring the same cells into P14/RAG−/− mice, whereas EP occurred in both recipients. Independent of CFSE dilution T cells developed CD44^bright phenotype after transfer into RAG−/− as well as in P14/RAG−/− mice as early as day 5, whereas the host P14tg CD8+ clone kept its naïve phenotype.

Applying our model on the CD4+ T-cell-induced colitis model, we found HP to play a pivotal role in induction of colitis. Despite the notion of EP being triggered by antigens from the bowel, colitis was only induced when HP occurred, independent of the occurrence of EP. In detail CD4+ T cells induced colitis 10 weeks after transfer into RAG−/− mice (EP and HP). However neither RAG−/− mice transplanted with CD8+ T cells nor P14/RAG−/− mice transplanted with CD4+ T cells (only EP) developed any signs of colitis. In addition the treatment with or without antibiotics during these 10 weeks did not influence on the induction of colitis.

We therefore conclude that the lymphopenia-mediated colitis after transfer of polyclonal CD4+ T cells correlates only with the occurrence of homeostatic proliferation. Furthermore the absence of regulatory CD4+CD25+ T cells within the suppressing P14 tg CD8+ clone indicates HP-induced colitis to be mediated by competition for cytokines or self-MHC stimulus. These findings might be of important relevance for research concerning chronic inflammatory bowel disease and donor lymphocyte induced colitis.