Elsevier

Immunology Letters

Volume 93, Issues 2–3, 15 May 2004, Pages 159-162
Immunology Letters

The spectrum of lymphoid subsets preferentially recruited into the liver reflects that of resident populations

https://doi.org/10.1016/j.imlet.2004.03.007Get rights and content

Abstract

Intrahepatic lymphocytes (IHL) differ phenotypically from cells found in the peripheral blood or in lymphoid organs. The liver contains T-cells that are also found in lymphoid organs but a higher proportion of these T-cells compared to those in lymphoid organs express activation or memory markers and very few naı̈ve T-cells are present within the liver. Furthermore, subsets such as NK and NK T-cells, which are detected at comparably lower levels within the lymphoid organs are increased within the liver.

To investigate whether a preferential recruitment of certain lymphoid subsets from the circulation contributes to the composition of intrahepatic lymphocytes, we compared their frequency in the liver with their organ tropisms. CFSE-labeled murine lymphoid cells were injected intravenously and their distribution within liver and spleen was analyzed after 24 h. Especially CD45RBlow memory T-cells, NK and NK T-cells, which are also present at high proportions within IHL, became predominantly recruited into the liver. In contrast, subsets such as naı̈ve CD62Lhigh T-cells and B-cells, which are predominantly represented within the lymphoid organs, preferentially migrated into the spleen.

These findings indicate that the pattern of migratory preferences reflects the representation of various subsets within the intrahepatic lymphocytes surprisingly well, suggesting that the composition of intrahepatic lymphocytes is largely shaped by the dynamics of entry and exit of cells into the organ.

Introduction

The liver harbors a distinct spectrum of lymphoid cells that differs from that found within lymphoid organs. Within the conventional T-cell population of the murine liver, activated CD62Llow subsets, cytokine producing effector and CD45RBlow memory cells as well as cells displaying markers of impending apoptosis are over-represented compared with lymphoid organs, similar to the composition of the cell population found in human liver [1], [2]. The unconventional lymphoid cells within the liver comprise a relatively large fraction of NK and NK T-cells. The latter can be subdivided into a majority of “classical” NK T-cells with a TCRαβ-phenotype and a much smaller subset of “non-classical” NK T-cells that might express a γδTCR or are CD8+ NK T-cells. As described for humans, murine classical NK T-cells display a restricted TCR repertoire, use an invariant Vα chain (Vα14Jα281) and recognize antigens in the context of CD1d. Most of these cells can be detected by their reactivity to the glycolipid α-GalCer-CD1d-tetramers [3], [4], [5], [6].

So far, various hypotheses to explain the origin and unique composition of IHL have emerged. One hypothesis assumes a local, thymus-independent origin, especially for the unconventional subsets within IHL, postulating that NK and NK T-cells do not belong to the recirculating pool of lymphoid cells [7]. An alternative model predicts an intrahepatic expansion and modulation of cells that might have been previously recruited into the liver, and it is this model is particularly suitable to explain the elevated frequency of activated and dying subfractions among conventional, recirculating T-cells within IHL [8].

In the following study, we present evidence that subsets that are over-represented within the liver compared to lymphoid organs, subsets such as memory, NK and NK T-cells becoming preferentially recruited into the liver from the circulation. These findings argue for recruitment as an important factor shaping the composition of IHL.

Section snippets

Antibodies

Labeled antibodies against surface markers were, if not indicated otherwise, purchased from BD Pharmingen, Heidelberg, Germany. Anti-FcRII/III (2.4G2) was kindly provided by the Deutsches Rheumaforschungszentrum, Berlin, Germany. Rat IgG was purchased from Sigma, Deisenhofen, Germany.

Reagents

Collagenase IV and DNAse I were purchased from Sigma, Deisenhofen, Germany. Metrizamide and Nycodenz were obtained from Nykomed, Norway. CFSE was obtained from MoBiTec, Göttingen, Germany.

Mice

BALB/c mice (8–10 weeks of

Results and discussion

Intravital microscopy and other techniques have demonstrated that subsets of lymphocytes continuously enter the liver from the bloodstream and remain trapped for some time in the organ, eventually leaving it later either directly or via draining lymph nodes [9]. This implies that a major part, if not the majority of IHL represents a recirculating, dynamic population. If so, a preferential recruitment of those subsets dominating the composition of IHL should be expected. We therefore first

Acknowledgements

We are grateful to Robert Hurwitz and S.H.E. Kaufmann (Max-Planck-Institute of Infection Biology, Berlin) for providing the αGal-Cer tetramers for detection of NK T-cells. Part of this work received financial support from the Deutsche Forschungsgemeinschaft, SFB 421 and SFB 633, awarded to A. Hamann and to K. Klugewitz, respectively.

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