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Comment on "Cutting Edge: Anti-CD25 Monoclonal Antibody Injection Results in the Functional Inactivation, Not Depletion, of CD4⁺CD25⁺ T Regulatory Cells"

Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom

In a recent article, Kohm et al. (1) make a case for the in vivo administration of anti-CD25 leading to a functional inactivation of CD4⁺CD25⁺ regulatory T cell (Treg), rather than their deletion as has been previously assumed. The majority of the data in the Kohm et al. article comes from the use of the 7D4 (rat IgM) Ab. We believe it is important to emphasize that, overwhelmingly, "Treg depletion" studies use a different clone, PC61 (rat IgG1). Kohm et al. suggest that down-modulation of CD25 after Ab treatment could lead to a misinterpretation that CD25-expressing cells are removed. This may be the case when using 7D4. However, using FACS analysis at the single cell level, we have previously reported that PC61 administration leads to a rapid and dramatic loss of CD25⁺Foxp3⁺ cells without a corresponding increase in CD25^–Foxp3⁺ cells (2). These data lead inevitably to the conclusion that the commonly used PC61 Ab does, in fact, deplete CD25-expressing Treg.

So we are left with the interesting situation of two anti-CD25 Abs having very different effects. This is perhaps not surprising given their difference in isotype. These differences seem to be reflected in disease. Kohm et al. have previously reported that 7D4 does not influence the course of experimental autoimmune encephalomyelitis (EAE) after optimal immune priming (3, 4), whereas their most recent data do show exacerbation when priming is suboptimal (1). In contrast, we and others have found PC61 treatment to exacerbate/prolong EAE after both optimal and suboptimal priming (2, 5, 6, 7). As a whole, these studies indicate that Treg do have a controlling influence over optimal disease, and their removal using PC61 allows for an increase in severity and/or failure to recover. 7D4 appears not to achieve this, but perhaps perturbs the Treg/T-aggressor balance sufficiently to allow the conversion of silent autoimmunity into overt autoaggression in the setting of suboptimal priming. It will be important to dissect the mechanisms underlying disease modification in both these settings.

References

1. Kohm, A. P., J. S. McMahon, J. R. Podojil, W. S. Begolka, M. DeGutes, D. J. Kasprowicz, S. F. Ziegler, S. D. Miller. 2006. Cutting edge: anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4⁺CD25⁺ T regulatory cells. J. Immunol. 176: 3301-3305. [Abstract/Free Full Text]
2. Stephens, L. A., D. Gray, S. M. Anderton. 2005. CD4⁺CD25⁺ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc. Natl. Acad. Sci. USA 102: 17418-17423. [Abstract/Free Full Text]
3. Kohm, A. P., J. R. Podojil, J. S. Williams, J. S. McMahon, S. D. Miller. 2005. CD28 regulates glucocorticoid-induced TNF receptor family-related gene expression on CD4⁺ T cells via IL-2-dependent mechanisms. Cell. Immunol. 235: 56-64. [Medline]
4. Kohm, A. P., J. S. Williams, A. L. Bickford, J. S. McMahon, L. Chatenoud, J.-F. Bach, J. A. Bluestone, S. D. Miller. 2005. Treatment with nonmitogenic anti-CD3 monoclonal antibody induces CD4⁺ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. J. Immunol. 174: 4525-4534. [Abstract/Free Full Text]
5. McGeachy, M. J., L. A. Stephens, L. A., and S. M. Anderton. 2005. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4⁺CD25⁺ regulatory cells within the central nervous system. J. Immunol. 175: 3025–3032.
6. Montero, E., G. Nussbaum, J. F. Kaye, R. Perez, A. Lage, A. Ben-Nun, I. Cohen. 2004. Regulation of experimental autoimmune encephalomyelitis by CD4⁺, CD25⁺ and CD8⁺ T cells: analysis using depleting antibodies. J. Autoimmun. 23: 1-7. [Medline]
7. Zhang, X., D. N. Koldzic, L. Izikson, J. Reddy, R. F. Nazareno, S. Sakaguchi, V. K. Kuchroo, H. L. Weiner. 2004. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25⁺CD4⁺ regulatory T cells. Int. Immunol. 16: 249-256. [Abstract/Free Full Text]

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