In the present study, both HIV-infected patients and patients with ICL showed evidence of translocation of microbial products, including elevated plasma levels of LPS and sCD14, compared with control subjects. Furthermore, increased activation and cycling of peripheral CD4 T cells were observed in both CD4 lymphopenic states. Strong associations of LPS levels and T cell proliferation with loss of naive CD4 T cells were also observed. These data support the notion that, in individuals with CD4 lymphopenia, including HIV-infected individuals, translocation of microbial products may play an integral role in lymphopenia-induced proliferation and chronic immune activation, or it may simply be the result of CD4 T lymphopenia either in the gut or in the lymphoid tissue.
HIV or SIV infection causes massive CD4 T cell depletion in the gut mucosa [15
]. High levels of LPS have been observed both in chronic HIV infection and in pathogenic SIV infection of RMs [8
]. The causal chain of events, however, is not entirely clear. In SIV infection of sooty mangabeys (SMs) or African green monkeys (AGMs), which are natural hosts for SIV that typically remain asymptomatic and do not experience progression to AIDS, there is evidence of CD4 T cell depletion in the gut [7
]. However, SMs and AGMs exhibit low levels of systemic T cell activation, proliferation, and bystander apoptosis during chronic infection. Furthermore, plasma LPS levels in SMs and AGMs are not elevated during chronic infection [7
]. More recently, the potential role of Th17-producing CD4 T cells in maintaining the integrity of the gut mucosa and/or clearance of bacterial products has been investigated. Both in SIV-infected RMs and in patients with chronic HIV infection, there is evidence of preferential depletion of Th17 CD4 T cells in the gut [23
]. In contrast, Th17 production in the gut appears to be preserved during SIV infection of SMs, suggesting that, with regard to pathogenesis, there might be an association between CD4 T cells producing IL-17 and LPS in the plasma [23
]. There are no data regarding T lymphocyte composition in the lymphoid tissues and/or gastrointestinal mucosa of patients with ICL. However, it is unlikely that the loss of CD4 T cells is restricted to peripheral blood in patients with ICL.
The fact that translocation of antigenic stimuli may not always be a direct consequence of gut mucosal CD4 T cell depletion led us to study the potential role of CD4 Th17 cells in patients with ICL. Th17 cells express various cytokines, including IL-17, TNF-α, and IL-6, and possess antibacterial and antifungal properties. Both HIV-infected patients and patients with ICL, however, appear to maintain a similar Th17 cellular response to mitogenic stimuli in the periphery, compared with healthy control subjects. This hypothesis will need to be further studied by characterizing the immunophenotype and Th17 functional responses of T cells at the level of the gut and other mucosal sites.
In contrast to HIV-infected participants, patients with ICL did not have evidence of profound CD8 T cell activation. The finding of similar LPS levels in individuals with either of the 2 conditions (HIV infection and ICL) but very different levels of CD8 T cell activation suggests that factors in addition to microbial translocation lead to immune activation in HIV-infected individuals [8
]. It is plausible that intermediary steps of the innate immune response may be vastly different in HIV-infected patients, compared with patients with ICL. Alternatively or in concert, tissue destruction, such as the collagen deposition that has been described in HIV infection [27
], may lead to aberrations of the T cell responses because of restricted supply of cytokines or other proliferative stimuli. The lack of studies of lymph nodes or mucosal sites in patients with ICL significantly limits our ability to draw any firm conclusions.
It is possible that aberrant immune activation induced by microbial products in subjects with lymphopenia may be playing an important—and even beneficial—role in lymphocytopenia-induced proliferation. Previous studies have shown that polyclonal T cells injected into severe combined immunodeficiency (SCID) mice raised under conventional environments gave rise to a more prominent population of rapidly proliferating cells than did T cells injected into SCID mice raised under germ-free conditions [20
]. Other studies involving murine models have shown that highly reactive exogenous agonist peptide–MHC complexes are required for activating naive T cell differentiation in effector cell phenotypes in lymphopenic mice [28
]. These findings suggest that, although self-peptides may be sufficient for T cell proliferation in lymphocytopenia-induced proliferation, exposure to foreign antigens, such as microbial products, could enhance the rate of homeostatic proliferation and activation.
In summary, our results suggest that translocation of microbial products is associated with perturbation of CD4 homeostasis in lymphopenic states other than HIV infection. Further definition of the mechanisms of immune activation in patients with ICL could help differentiate anticipated compensatory mechanisms of T cell turnover from the deleterious influence of HIV infection on T cell homeostasis.