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Comment on "Germinal Center Helper T Cells Are Dual Functional Regulatory Cells with Suppressive Activity to Conventional CD4⁺ T Cells"

Division of Hematology, Azienda Ospedaliera Universitaria Santa Chiara, Pisa, Italy

Marinova et al. (1) show that germinal center (GC) CD4⁺CD57⁺ T cells represent a novel population of regulatory T cells that express CTLA-4 and glucocorticoid-induced TNF receptor but not FOXP3. Although they help GC B cells, these cells inhibit CD4⁺CD57^– memory/effector T cells via IL-10, TGF-, and CD95-CD95L interaction. In 2005, Kim et al. (2) showed that CD4⁺CD45RO⁺CD45RA^–CD57⁺CCR7^–CXCR5⁺ T cells in the GC of human lymphoid tissues comprise the major T cell subset that helps GC B cells produce immunoglobulins, acting via CD40L.

However, contrary evidence exists. In 1995, Bouzahah et al. (3) showed that human tonsillar CD4⁺CD57⁺ T cells, which mainly occupy the light zones of the GC where few B cells divide, did not markedly enhance B cell proliferation, contrary to GC CD4⁺CD57^– T cells. In 1996, Andersson et al. (4) showed that the addition of exogenous IL-2 was required for induction of Ig production by CD4⁺CD57⁺ GC helper T cells in vitro, although these cells spontaneously rescued GC B cells from cell death.

In 2006, Rasheed et al. (5) showed that in GC T cells from human tonsils, differences in stimulatory activity and CXCL13 secretion were related only to the expression levels of the homeostatic chemokine receptor CXCR5 and the costimulatory molecule ICOS, indicating that CD57 does not serve as a surrogate marker for helper activity. Even if we agree that the morphological interrelations between CD4⁺CD57⁺ GC T cells and follicular dendritic cells (as first described in 1989 by Yuda et al. (6)) and the appearance of CD57⁺ cells during the transition from the primary follicle to the GC can be misleading, Marinova et al. should have made clear to readers that they were investigating a cell population that lacks the optimal surrogate markers for GC B cell help.

References

1. Marinova, E., S. Han, B. Zheng. 2007. Germinal center helper T cells are dual functional regulatory cells with suppressive activity to conventional CD4⁺ T cells. J. Immunol. 178: 5010-5017. [Abstract/Free Full Text]
2. Kim, J., H. Lim, S. Kang, P. Hillsamer, C. Kim. 2005. Human CD57⁺ germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination. BMC Immunol. 6: 3[Medline]
3. Bouzahzah, F., A. Bosseloir, E. Heinen, L. Simar. 1995. Human germinal center CD4⁺CD57⁺ T cells act differently on B cells than do classical T-helper cells. Dev. Immunol. 4: 189-197. [Medline]
4. Andersson, E., K. Dahlenborg, M. Ohlin, C. Borrebaeck, R. Carlsson. 1996. Immunoglobulin production induced by CD57⁺ GC-derived helper T cells in vitro requires addition of exogenous IL-2. Cell Immunol. 169: 166-173. [Medline]
5. Rasheed, A., H. Rahn, F. Sallusto, M. Lipp, G. Muller. 2006. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36: 1892-1903. [Medline]
6. Yuda, F., K. Terashima, M. Dobashi, M. Ishikawa, Y. Imai. 1989. Ultrastructural analysis of HNK-1⁺ cells in human peripheral blood and lymph nodes. Histol. Histopathol. 4: 137-152. [Medline]

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				E. Marinova, S. Han, and B. Zheng Response to Comment on "Germinal Center Helper T Cells Are Dual Functional Regulatory Cells with Suppressive Activity to Conventional CD4+ T Cells" J. Immunol., July 15, 2007; 179(2): 731 - 732. [Full Text] [PDF]

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