Decimation of the T-cell pool following intensive chemotherapy, bone marrow transplantation, or infection with HIV renders the patient highly susceptible to a variety of life-threatening infectious pathogens and/or fatal malignancies. Restoration of normal T-cell immunity can occur by 2 distinct paths: The first is an educational process whereby now-naı̈ve T-cell precursors in the bone marrow traffic through the thymus to acquire the diverse receptor repertoire necessary to face the multitude of pathogens. The second pathway relies on the few surviving T-cell soldiers in the blood, wounded and fragile but with the potential to regroup and expand into a competent lymphocyte pool in the absence of a thymus. How these few peripheral T cells can avoid remedial education in the thymus, survive, and grow to contribute to host immune restoration has remained a mystery. Fry and colleagues (page 1525) examine restoration of T-cell immunity in the absence of thymic education. They demonstrate that, in thymectomized mice receiving exogenous IL-7, low numbers of peripheral T cells can attack target antigens via at least 3 mechanisms: better T-cell expansion, enhanced T-cell survival, and improvement in target antigen–presenting cells. The absence of exogenous IL-7 renders the thymectomized host unable to recognize the target antigen.

This has potentially exciting clinical application in adults with T-cell deficiencies and a restricted amount of thymic function. Should the study results in the mouse model of HY-disparate skin grafts prove comparable in models of high-dose chemotherapy, one could soon envision clinical trials of high-dose chemotherapy followed by low-dose IL-7 therapy to assess the cytokine's effect on quantitative and qualitative aspects of peripheral-T-cell reconstitution. More effective T-cell recovery in states of minimal residual malignant disease that often follow high-dose chemotherapy might impact on disease-free and overall survival. Comparable studies in the setting of allogeneic transplantation would need to balance the possible advantages of improved T-cell function in combating life-threatening infections and in mediating graft-versus-tumor effects with the potential adverse consequences of intensifying graft-versus-host disease or graft rejection. But in patients with HIV infection on effective antiretroviral therapy, low-dose IL-7 therapy might contribute to a more sustained and diverse T-cell recovery by enhancing both the proliferative response and the threshold for apoptosis.