SEARCH:   Advanced

Blood, 23 July 2009, Vol. 114, No. 4, pp. 751-752. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Sereti, I. PubMed PubMed Citation Articles by Sereti, I. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Beq et al, page 816 Where have all the T cells gone? Irini Sereti NATIONAL INSTITUTES OF HEALTH In this issue of Blood, Beq and colleagues describe the massive yet transient exodus of T cells from peripheral blood to lymph nodes, skin, and gut lymphoid tissue after in vivo IL-7 administration to healthy Rhesus macaques.1 This dramatic brief T-cell lymphopenia has previously been described in both cancer and HIV clinical trials of rhIL-7.2,3 Tissue redistribution of T lymphocytes had been invoked to explain this unusual occurrence but there was no data supporting this hypothesis until now. Beq et al follow healthy Rhesus macaques after administration of recombinant simian (rs) interleukin (IL)–7 with repeat sampling of peripheral blood and tissues, measuring apoptosis, expression of chemokine receptors in CD4 and CD8 T-cell subsets, and chemokine levels in tissues and plasma. Their results show lack of increased apoptosis after rsIL-7 administration but significant up-regulation of homing chemokine receptors on T cells including CXCR4, CCR6, and CCR9 coupled with increased chemokine levels in tissues (CCL19, CCL20, CCL21, and CCL25) and plasma (CCL3, CCL4, and CXCL12). The physiologic significance of these observations was demonstrated by T- lymphocyte infiltration in lymph nodes, gut and skin lymphoid tissue. T-cell cycling, a known outcome of IL-7 administration, was noted in these same tissues prior to detection of cycling T cells in the peripheral blood. This work is important for many reasons: (1) it provides us with data supporting tissue redistribution as the explanation of lymphopenia observed in recombinant human (rh) IL-7 clinical trials; (2) it shows potential mechanisms that could account for some of the side effects observed in preclinical and clinical studies of IL-7, specifically skin rashes, diarrhea, and possibly the elevation of liver enzymes (however, no liver biopsies were shown); (3) it gives insight into the homing of T cells in response to homeostatic cytokine signals that are relevant in both normal and lymphopenic conditions; (4) it shows that IL-7 induces T-cell cycling in lymph nodes, skin and gut, suggesting that the T-cell expansions seen in rhIL-7–treated subjects occur at the tissue level and are not due to redistribution; and (5) it suggests mechanisms that could explain lack of response to endogenous or exogenous IL-7 such as destruction of tissue or lymph node architecture or disruption of chemokine receptor-chemokine interactions. Finally, the study also highlights our shortcomings in assessing total body lymphocytes by demonstrating how peripheral blood T lymphocyte observations may not be representative and may even be misleading in disease states characterized by altered levels of cytokines, chemokines, and chemokine receptor expression. Some questions remain: Why didn't CCR7 (an important molecule for homing to lymph nodes) increase on T cells? Why were there no increases of CD3+ cells in lymph node biopsies at 24 hours despite demonstrable increases in Ki67 expression? Why were there significant differences in chemokine receptor expression between CD4 and CD8 T cells despite identical disappearance and recovery rates from the circulation? Nevertheless, this type of detailed work with frequent peripheral blood and tissue sampling would not be possible in a clinical study. Although the authors contrast their observations to the IL-2 effects, suggesting that apoptosis explained the lymphopenia induced by IL-2, one could argue that similar trafficking phenomena may also have occurred in IL-2–treated subjects, in addition to the enhanced apoptosis that followed the observed lymphopenia.4 Better understanding of the mechanisms of action of cytokines can help interpret clinical observations, improve future clinical study designs, ameliorate concerns about lymphopenia or other transient side effects, and further elucidate the role of cytokines in normal T-cell homeostasis and lymphopenia. Phase 1 clinical studies of rhIL-7 have shown significant expansion of both CD4 and CD8 T-cell subsets, suggesting a potential role for rhIL-7 in treatment of lymphopenic diseases such as HIV infection.3,5 After the recent failure of IL-2 to show any clinical benefit in large phase III clinical trials in HIV infection6,7 despite significant CD4 T-cell increases, it will be essential to demonstrate that cytokine-induced T-cell expansions in peripheral blood reflect a normal T-cell tissue distribution and function with a diverse T-cell repertoire. Acknowledgment This work was supported by the Intramural Research Program of the NIH, NIAID. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Beq S, Rozlan S, Gautier D, et al. Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques. Blood. 2009;114:816–825.[Abstract/Free Full Text] Sportes C, Hakim FT, Memon SA, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205:1701–1714.[Abstract/Free Full Text] Sereti I, Dunham RM, Spritzler J, et al. IL-7 administration drives T cell cycle entry and expansion in HIV-1 infection. Blood. 2009;113:6304–6314.[Abstract/Free Full Text] Sereti I, Herpin B, Metcalf JA, et al. CD4 T cell expansions are associated with increased apoptosis rates of T lymphocytes during IL-2 cycles in HIV infected patients. AIDS. 2001;15:1765–1775.[CrossRef][Medline] [Order article via Infotrieve] Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009;119:997–1007.[Medline] [Order article via Infotrieve] Losso M, Abrams D. Effect of IL-2 on clinical outcomes in patients with a CD4+ cell count of 300/mm3. Primary results of the ESPRIT study. Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, February 10, 2009. Paper presented at:. Levy Y. Effect of IL-2 on clinical outcomes in patients with a CD4+ cell count 50–299 cells/mm3. Primary results of the SILCAAT study. Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, February 10, 2009. Paper presented at:. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques Stéphanie Beq, Sandra Rozlan, David Gautier, Raphaëlle Parker, Véronique Mersseman, Clémentine Schilte, Brigitte Assouline, Iann Rancé, Pascal Lavedan, Michel Morre, and Rémi Cheynier Blood 2009 114: 816-825. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Sereti, I. PubMed PubMed Citation Articles by Sereti, I. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020