Where have all the T cells gone?

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 infection^6,7  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.