Fully Immunocompetent CD8+ T Lymphocytes Are Present in Autologous Haematopoietic Stem Cell Transplantation Recipients Despite an Ineffectual T-Helper Response

BACKGROUND: Reduced CD4 T lymphocytes counts can be observed in HIV infection and in patients undergoing autologous haematopoietic stem cell transplantation (ASCT). Nevertheless, whereas opportunistic infections (OI) are frequent in HIV-infected individuals with low cell counts, OI are uncommon in ASCT patients. METHODOLOGY/PRINCIPAL FINDINGS: To verify whether this observation could be secondary to intrinsic HIV-correlated T cell defects, we performed in-depth immunologic analyses in 10 patients with comparable CD4 counts in whom lymphopenia was secondary either to HIV-infection or ASCT-associated immunosuppressive therapy and compared them to age-matched healthy subjects. Results showed the presence of profound alterations in CD4+ T lymphocytes in both groups of patients with respect to healthy controls. Thus, a low percentage of CCR7+ CD4+ T cells and a compensative expansion of CD45RA-CCR7- CD4+ T cells, a reduced IL-2/IFN-gamma cytokine production and impaired recall antigens-specific proliferative responses were detected both in ASCT and HIV patients. In stark contrast, profound differences were detected in CD8+ T-cells between the two groups of patients. Thus, mature CD8+ T cell prevailed in ASCT patients in whom significantly lower CD45RA-CCR7- cells, higher CD45RA+CCR7- CD8+ cells, and an expansion of CCR7+CD8+ cells was detected; this resulted in higher IFN-gamma +/TNFalpha production and granzyme CD8+ expression. The presence of strong CD8 T cells mediated immune responses justifies the more favorable clinical outcome of ASCT compared to HIV patients. CONCLUSION/SIGNIFICANCE: These results indicate that CD8 T cells maturation and functions can be observed even in the face of a profound impairment of CD4+ T lymphocytes in ASCT but not in HIV patients. Primary HIV-associated CD8 defects or an imprinting by an intact CD4 T cell system in ASCT could justify these results

CD8+ T cell maturation patterns lymphocytes in ASCT recipients (ASCT), in HIV-infected patients (HIV) and healthy controls (HC).

<p>The percentage of <i>naïve</i> CD8+ T cells (CD45RA+CCR7+) (A), <i>central memory</i> (CD45RA−CCR7+) (B), <i>effector memory</i> (CD45RA−CCR7−) (C) and <i>effector</i> cells (CD45RA+CCR7−) (D) were compared in the groups. Higher levels of <i>naïve</i> CD8+ T-cells were observed in ASCT recipients compared to HIV+ patients. Whereas in HIV positive patients <i>effector memory</i> CD8+ T cells were the predominant memory phenotype, in ASCT recipients significantly higher levels of CD45RA+CCR7− <i>effector</i> CD8+ cells were evidenced. Each central bar represents the median value and each box corresponds to the 25^th through 75^th percentile (interquartile) range.</p

Ratios of CD4+ and CD8+ lymphocytes subsets across ASCT recipients (ASCT), HIV-infected patients (HIV) and healthy controls.

<p>ASCT recipients and HIV-infected patients displayed similar ratios between CD4+ subpopulations, CD45RA−CCR7+(CM)/CD45RA−CCR7− (EM). CD45RA−CCR7−CD8+(EM)/CD45RA+CCR7−CD8+(TD) ratio was significantly lower in ASCT recipients compared to HIV+ patients, with no differences in CD45RA−CCR7+ CD8+ (CM)/CD45RA−CCR7− CD8+ (EM) and CD45RA−CCR7+ CD8+ (CM)/ CD45RA+CCR7−CD8+ (TD) ratios among the two group of patients.</p

Characteristics of the ASCT (Group A) and HIV-infected patients (Group B).

<p>Characteristics of the ASCT (Group A) and HIV-infected patients (Group B).</p

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).

<p>ASCT recipients displayed significantly higher levels of TNF-α and IFN-γ producing CD8+ T cells under basal conditions and of TNF-α+ CD8+ T cells under <i>Staphylococcal</i> β enterotoxin (SEB) stimulation compared to HIV-infected patients. CD4+ IL-2 and IFN-γ 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.</p

Phenotypical maturation pattern of CD4+ lymphocytes in ASCT recipients (ASCT), HIV-infected patients (HIV) and healthy controls (HC).

<p>The percentage of <i>naïve</i> CD4+ T cells (CD45RA+CCR7+) (A), <i>central memory</i> (CD45RA−CCR7+) (B), <i>effector memory</i> (CD45RA−CCR7−) (C) and <i>effector</i> cells (CD45RA+CCR7−) (D) were compared in the groups. ASCT recipients and HIV-infected patients displayed low percentages of <i>naïve</i> and central <i>memory</i> CD4+ T cells. A relative expansion of <i>effector memory</i> cells was observed in both population. Each central bar represents the median value and each box corresponds to the 25^th through 75^th percentile (interquartile) range.</p