Lymphocytes in ASCT and HIV Figure 4. Cytokine CD4+ (A) and CD8+ (B) production, CD8+ lysis molecules expression (C) and lymphocyte proliferation (D) in ASCT recipients (ASCT), in HIV-infected patients (HIV) and in healthy controls (HC). ASCT recipients displayed significantly higher levels of TNF-a and IFN-c producing CD8+ T cells under basal conditions and of TNF-a+ CD8+ T cells under Staphylococcal b enterotoxin (SEB) stimulation compared to HIV-infected patients. CD4+ IL-2 and IFN-c production after SEB stimulation was globally depressed in both group of patients compared to healthy controls. The fraction of CD8+ T cells expressing granzyme B was higher in ASCT recipients than in HIV-infected patients. Antigen-induced proliferative responses showed comparable stimulation index values in both patients population and for polyclonal activation (PHA) as well as antigen stimulation (Flu, Candida), with significant difference with healthy controls regarding Flu stimulation. * = p,0.05 in the comparison between groups. doi:10.1371/journal.pone.0003616.g004 CD45RA2CCR72 effector memory CD4+ cells was observed. This phenotypic data well correlate with the results of our functional analysis, characterized by low IL-2/IFN-c producing CD4 T lymphocytes of highly impaired proliferative ability. In chronic viral infections, phenotypic and functional hetero- geneity of memory CD4 T cells responses is believed to be regulated by antigen persistence and high/low levels of antigen load. The monophenotypic CD45RA2CCR72 CD4 T cell responses typical of chronic and progressive HIV infection have not, in fact, been found in long term non-progressors, where a multi-phenotypic CD4 T cell response, typical of repetitive Ag exposure and low Ag load was present [16,23]. It is well known that lymphopenia is invariably associated with homeostatic expansion of the remaining T cells in the periphery, in response to endogenous MHC ligands and IL-7, but also with immune reactivity, both to self- and foreign antigens not normally apparent in T cell–replete hosts [28]. Consequentially, the explanation for the large compensative expansion of monopheno- typic CD45RA2CCR72 CD4 T cell responses in ASCT recipients could be a high antigenic exposure to self peptide, including tumor antigens [29], or, alternatively, to nonself peptides, such as normal flora in the gastrointestinal [GI] tract–gut commensals, that have been recognized as the dominant force for rapid proliferation of T cells in severely immunodeficient host [28]. In summary, our data show that CD4+ T-cell count deficiency in ASCT recipients is associated with skewed representation of memory CD4 T cells and cytokine and proliferative defects - an immune pattern surprisingly similar to that of HIV infection. In contrast to HIV-positive patients, however, CD8 T cells were normally distributed and were functionally intact in ASCT recipients 9 months after. The presence of high quantities of TNFa/IFNc-producing and granzyme-enriched effector CD8+ T cells, associated with the low rate of infectious mortality observed in ASCT recipients [8], suggest that even a T-cell compartment which is greatly impaired in CD4+ T cells number and function may provide protective immunity against opportunistic agents if it PLoS ONE | www.plosone.org 6 October 2008 | Volume 3 | Issue 10 | e3616