Email updates

Keep up to date with the latest news and content from Arthritis Research & Therapy and BioMed Central.

This article is part of the supplement: 25th European Workshop for Rheumatology Research

Poster presentation

Bystander-activated CD4+ memory lymphocytes: a role in the pathology of rheumatoid arthritis?

JT Beech, SH Owen, P Green, P Amjadi and FM Brennan

Author Affiliations

Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, London, UK

For all author emails, please log on.

Arthritis Research & Therapy 2005, 7(Suppl 1):P145  doi:10.1186/ar1666

The electronic version of this article is the complete one and can be found online at:


Received:11 January 2005
Published:17 February 2005

© 2005 BioMed Central Ltd

Background

Previous studies in this laboratory have highlighted the importance of the proinflammatory cytokine tumour necrosis factor alpha (TNF-α) in the pathogenesis of rheumatoid arthritis (RA) and suggested a role for bystander-activated lymphocytes in its chronic production in the RA joint. Normal peripheral blood (PB) lymphocytes cultured in the presence of a 'cocktail' of inflammatory cytokines (IL-2/IL-6/TNF-α) generated effector cells (TCK) capable of inducing both immunoglobulin production by B cells [1] and TNF-α production by monocytes in a contact-dependent manner. This was in contrast to lymphocytes activated antigen dependently, via the T-cell receptor (TTCR), which induced production of both TNF-α and the anti-inflammatory cytokine IL-10 [2,3]. Lymphocytes isolated from the RA synovial membrane exhibited contact-dependent cytokine induction properties similar to TCK, not TTCR, cells [4].

Objective

We have examined the population dynamics and phenotypic changes induced in PB lymphocytes during culture with IL-2/IL-6/TNF-α to determine how such cells resemble those found in the RA joint. As the predominant infiltrating lymphocyte population found to accumulate in the RA synovial membrane is the CD4+ T cell we have also explored the possibility of generating monocyte TNF-α-inducing effector cells from purified CD3+CD4+ populations.

Results

Lymphocytes cultured with IL-2/IL-6/TNF-α over 8 days demonstrated a threefold expansion of the natural killer cell population, while the proportion of T cells remained static. However, both these natural killer and T-lymphocyte populations were independently able to induce contact-dependent TNF-α production in monocytes. Interestingly, effector cells generated by culture of the purified CD3+CD4+ fraction with IL-2/IL-6/TNF-α for 8 days were able to induce at least threefold more TNF-α production compared with such effectors generated from the corresponding unfractionated lymphocyte population. We subsequently characterised the different naïve and memory cell populations found within the CD4+ fraction of our bystander-activated lymphocyte cultures (as defined by Lanzavecchia and colleagues [5]). Despite an overall net loss in the percentage and number of total CD4+ T cells, both naïve (CD45RA+CCR7+) and memory populations (effector:CD45RO+CRR7-; central CD45RO+CCR7+) were still present after 8 days of culture. However, a preferential retention of effector memory over central memory lymphocytes has been observed in most donors.

Further phenotypic studies have shown that bystander-activated lymphocytes also express high levels of components of the adhesion molecules VLA-1, VLA-4, VLA-5 and LFA-1 (β1, β2 and α4), but lower levels of L-selectin (CD62L). Such properties are associated with the ability of effector lymphocytes to migrate from lymph nodes and into tissues.

Conclusions

Our results suggest that exposure of PB lymphocytes to a cocktail of proinflammatory cytokines induces the outgrowth of an activated effector memory lymphocyte population with the capacity to migrate to inflammatory sites. Studies currently underway will examine the effector function of different CD4+ subsets in terms of their ability to induce monocyte TNF-α production.

This work will more closely define pivotal cell types responsible for cognate-dependent cytokine production in diseased joints as well as advancing our understanding of the effects and consequences of prolonged cytokine exposure in chronic inflammation.

Acknowledgement

This work was funded by the Arthritis Research Campaign, UK.

References

  1. Unutmaz D, Pileri P, Abrignani S: Antigen-independent activation of naive and memory resting T cells by a cytokine combination.

    J Exp Med 1994, 180:1159-1164. PubMed Abstract | Publisher Full Text OpenURL

  2. Sebbag M, Parry SL, Brennan FM, Feldmann M: Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: possible relevance to pathophysiology of rheumatoid arthritis.

    Eur J Immunol 1997, 27:624-632. PubMed Abstract OpenURL

  3. Parry SL, Sebbag M, Feldmann M, Brennan FM: Contact with T cells modulates monocyte IL-10 production: role of T cell membrane TNF-alpha.

    J Immunol 1997, 158:3673-3681. PubMed Abstract | Publisher Full Text OpenURL

  4. Brennan FM, Hayes AL, Ciesielski CJ, Green P, Foxwell BM, Feldmann M: Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: involvement of phosphatidylinositol 3-kinase and nuclear factor kappaB pathways in tumor necrosis factor alpha production in rheumatoid arthritis.

    Arthritis Rheum 2002, 46:31-41. PubMed Abstract | Publisher Full Text OpenURL

  5. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.

    Nature 1999, 401:708-712. PubMed Abstract | Publisher Full Text OpenURL