What limits immune reconstitution in HIV infection? Divergent tools converge on thymic function (2001)

The developmental pathways through which T cells are generated has been one of the most intensely studied areas of immunology, but progress in understanding the regeneration of T cells in humans following profound T cell depletion has been relatively slow. In the last few years, however, numerous human-based studies evaluating immune reconstitution in varied clinical populations with T cell depletion have shed new light on human T cell regeneration. It is now generally accepted that T cell populations are restored in humans through a combination of thymic-dependent regeneration and the simultaneous peripheral expansion of residual mature T cells and new thymic emigrants. This progress has been driven largely by the development of varied tools, which are now available to measure thymic function and to quantitate T cell turnover as a rough measure of peripheral expansion. Methods used to measure thymic function include quantification of cells bearing a naive phenotype [1,2], thymic imaging [2,3], measurement of T cell receptor excision circle (TREC) levels [4] and broadening of T cell receptor repertoire diversity [5,6]. Tools used to measure T cell turnover include evaluation of telomere length [7], direct measurement of T lymphocyte production/turnover rates [8] and evaluation of the T cell activation that occurs during peripheral expansion [9]. Each of these procedures, if used alone, is potentially flawed in and of itself; hence such results should be interpreted with caution. For example, compute tomographic (CT) scans of the thymus cannot distinguish between infiltrative secondary lymphoid tissue within the perivascular space and a functioning thymic microenvironment within the thymic epithelial space [10]. Using phenotype to quantify naive populations is problematic since it is never clear that an individual cell bearing a naive cell phenotype represents a true thymic emigrant or a revertant from a previous memory clone [11]. Levels of TREC, which provide direct evidence of T cell receptor rearrangement, are diluted through cell division occurring simultaneously with thymic output in diseases associated with T cell depletion; therefore, it is difficult to determine whether diminished TREC levels reflect reduced thymic function or increased peripheral expansion [12]. Similarly, parameters used to measure peripheral T cell turnover directly (deuterated glucose labeling) or indirectly (such as the phenotypic analysis of activated populations and measurement of telomere length) can suggest that immune reconstitution is occurring via peripheral expansion but generally cannot exclude T cell expansion as a consequence of specific immune activation, such as induced by HIV. Therefore, none of these tools when analyzed independently can provide a complete picture of the relative contribution of thymic-dependent and thymic-independent pathways of immune reconstitution. Nevertheless, today multiple tools can be used concurrently to study clinical populations with profound T cell depletion. The manuscripts by Steffens et al.[13] and Teixeira et al.[14] published in this edition of AIDS have done just that to study immune reconstitution in cohorts of HIV-infected individuals. Together, the data generated provide a compelling picture of successful immune reconstitution after highly active antiretroviral therapy (HAART) being dominated by thymic regenerative pathways. These results are most convincing because the authors used a variety of divergent techniques, such as TREC levels, CT scans and naive cell subsets, to arrive to the same conclusion: most patients who sustain adequate viral suppression through HAART are able to regenerate new T cells via thymic pathways. Importantly, individual analyses performed in each study correlated with one another, as would be expected. Thus, older patients with a lower thymic index by CT scanning show less naive cells and have less TREC compared with younger patients. Furthermore, diminished thymic function correlated with increased peripheral T cell activation and diminished telomere length, which would be expected when immune reconstitution is driven primarily by peripheral expansion [13,14]. With these findings as a backdrop, we can now begin to ask mechanistic questions regarding why the ‘immunologic recovery’ induced by HAART is not experienced by everyone. Using the tools discussed above, clinical subsets of patients can now be identified with impaired immunologic recovery following HAART that is related to diminished thymic function [14]. In addition to age as a risk factor for diminished thymic function, one can investigate whether poor thymic reserve relates to disease-associated factors (e.g., accumulated toxicities owing to HIV, therapy and/or intercurrent infections) or rather reflects a genetic predisposition in some individuals. One can also now address whether the problem of diminished thymic function relates to the fuel or the engine? In other words, is the sensor (e.g., cytokine, hormone) that drives immune reconstitution insufficient in patients with diminished thymic function or is the thymus itself unable to respond to thymopoietic signals? The lower levels of the stromal cell-derived cytokine interleukin 7 observed in poor immunologic responders suggests that the fuel may be limiting [15]. If a relative deficiency of interleukin 7 is the problem in a cohort of patients with poor immunologic recovery following HAART, then the therapeutic solution may lie in supplying the deficient cytokine. If, however, the problem is one of end-organ insensitivity, such as an inability of the thymus to respond to interleukin 7 and/or other thymopoietic signals, then efforts to restore thymic function in these patients will require other, more creative approaches.