Characterizing the Phenotype of Memory T cells in Cord Blood in Response to HIV-1 Pubblico
Howard, Chanie Lai (2014)
Abstract
Even in the absence of combination antiretroviral therapy, a relatively low risk of mother-to-child transmission of HIV-1 in utero is documented (7%), suggesting natural correlates of protection exist at the feto-maternal interface, either in the placenta or in the cord blood. Little has been done to characterize memory T cell populations in cord blood, in the absence and presence of activation, as a correlate of protection or surrogate of transmission, respectively, during on-going HIV-1 exposure. In primate studies, natural hosts have been shown to down regulate HIV-1 co-receptor (CCR5) expression on central memory T cells (Tcm) and maintain low levels of T cell activation during the chronic phase of SIV infection. Studies in humans have shown that CCR5 expression is largely restricted to memory cells. Interestingly, low levels of memory cells are found in infants compared to adults. In order to investigate possible mechanisms of natural protection against HIV-1 transmission within fetal cord blood, we examined HIV-1 co-receptor expression, immune activation and apoptosis on stimulated and unstimulated cord blood mononuclear cells (CBMCs). We hypothesize that the immune quiescent environment in cord blood may protect Tcm cells from HIV-1 infection by regulating CCR5 expression. Here we show lower fractions of memory T cell populations and CCR5 expression in CBMCs in contrast to adult peripheral blood mononuclear cells (PBMCs). This is despite comparable proliferative capacities in response to stimulation in both cell types. Post-stimulation, the fraction of Tcm cells in both CD4+ and in CD8+ T cells increases five-fold, while the unstimulated Tcm subsets remain unchanged. In addition, CCR5 expression is significantly upregulated under similar conditions. Intriguingly, CXCR4 (HIV-1 co-receptor) expression remained elevated in stimulated and unstimulated CD4+ Tcm cells post-infection. Lower levels of CCR5 expression in unstimulated CBMCs, independent of CXCR4 expression, may influence HIV entry and infection. In this regard, we show that HIV-1 replication is lower in unstimulated CBMCs compared to stimulated cells. High apoptotic levels are observed in stimulated Tcm cells post-infection. Taken together, these results suggest that the unstimulated (immune quiescent) environment in cord blood may protect central memory T cells from HIV-1 infection by regulating CCR5 expression.
Table of Contents
Introduction 1
Rationale for Study and Hypothesis 23
Methods 25
Results 28
Lower fraction of memory T cells in cord blood when compared to adult blood 28
Low levels of TCM maintained in unstimulated CD4+ T cells of CBMCs over time compared to a five-fold increase in stimulated CD4+ TCM levels over time 30
Low levels of TCM maintained in unstimulated CD8+ T cells of CBMCs over time compared to a six-fold increase in stimulated CD8+ TCM over time 31
Low levels of HIV-1 replication, measured by p24 levels, in unstimulated CBMCs compared to higher levels of HIV-1 replication in stimulated CBMCs 31
Rapid CD4+ T cell proliferation in CBMCS upon stimulation, but low CCR5 levels in unstimulated CBMCs compared to stimulated PBMCs 34
Similar levels of CXCR4 expression observed in both stimulated and unstimulated T cells of CBMCs over time 38
Reduced CCR5 expression in unstimulated T cells of CBMCs 40
CD4+ T cell death, CD4+ central memory T cell death in stimulated CBMCs 42
Discussion 44
Low levels of CD4+ and CD8+ central memory T cells in an unstimulated, quiescent immune environment 44
Downregulation of memory T cells post-infection serves as a possible correlate of protection against HIV-1 45
Lower levels of memory cells in cord blood compared to adult blood and similar levels of CXCR4 expression both unstimulated CBMCs and stimulated CBMCs 46
Low levels of CCR5 expression in cord blood correlates with lower HIV-1 infection 47
High levels of apoptosis in stimulated CD4+ T cells lead to loss of T cell homeostasis 48
Immune quiescence in the fetomaternal environment 50
Conclusion 51
References 53
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