Dr. Cairo received her PhD. in immunology in Rome, at the University of Rome Tor Vergata, Italy, after carrying out part of her graduate studies at the Institute of Human Virology. Since her graduate student's days, she has been interested in immunologic responses in human neonates and has taken active part in field studies in different African countries (Cote D'Ivoire, Cameroon, Nigeria and Malawi), which heavily influenced her research interests and her approach to research.
Dr. Cairo’s research is focused on innate immune responses to pathogens in human neonates and adults. The model population for our studies are human γδ T cells, innate-like lymphocytes that exert rapid effector function and contribute to regulating adaptive immune responses. γδ T cells, specifically Vγ9Vδ2 (Vδ2) lymphocytes, are at the interface between innate and adaptive immunity and respond to a broad range of microbes (including P. falciparum, M. tuberculosis and HIV). They express a rearranged TCR, but antigen recognition mediated by the Vγ9Vδ2 TCR does not require MHC-restriction. Consequently, Vδ2 cells mount effector responses in all individuals, regardless of HLA background. Activated Vδ2 cells produce abundant Th1 cytokines, differentiate into cytotoxic effectors, increase NK cell cytotoxicity, promote DC maturation, present and cross-present antigens to CD4+ and CD8+ T cells. Unlike CD4+ T cells, Vδ2 lymphocytes are already poised for rapid Th1 responses before birth. Moreover, they can use cytokines of myeloid origin, like IL-23 or IL-15, to sustain their own CD4-independent proliferation, which may be extremely valuable in the first few months of life, when the adaptive immunity is still maturing. Due to these features, Vδ2 lymphocytes play a key role as a first line of defense in infants and may be exploited to potentiate immune responses early in life. Our objective is to study the functional program of neonatal lymphocytes (including immune-regulatory mechanisms at the fetal maternal interface) and the impact of pathogen exposure before birth on the development of the infant immune system. Vδ2 cells represent a convenient model to examine functional responses and immuneregulation, because they can be easily expanded and differentiated in vitro. In addition, they are ideal for repertoire analyses due to the relatively limited diversity of the T cell receptor gamma repertoire.
One of Dr. Cairo’s projects focuses on the impact of prenatal exposure to P. falciparum (Pf) antigens on immunity to related and unrelated pathogens in neonates and infants. In general, in utero exposure to microbial antigens has the potential to alter responsiveness to early childhood vaccination and increase infant susceptibility to infections. In particular, prenatal exposure to Pf can increase susceptibility to malaria in infants and decrease early responses to mycobacterial antigens. The mechanisms leading to these long-term outcomes and the contribution of innate and “innate-like” cell populations are not well understood. Our preliminary data (generated by two pilot studies in Nigeria and Cameroon) suggested that prenatal exposure to placental malaria causes deletion of pathogen-reactive Vδ2 lymphocytes in the fetus and attenuates the expansion of these cells following antigen stimulation. We are now validating and extending these results in a larger study in Malawi where, in collaboration with Dr. M. Laufer, we enrolled women with a detailed history of Pf infection during pregnancy. Impaired neonatal Vδ2 cell functions might increase susceptibility to several pathogens and reduce responses to Bacille Calmette-Guerin (BCG), since Vδ2 cells take part in the response to this vaccine.
We recently identified a mechanism that may help explain the observations described above. PD1, a negative regulator of T and B cell responses, is a determinant of tolerance, in particular at the fetal-maternal interface. We observed that neonatal Vδ2 cells up-regulate PD1 shortly after activation in vitro and, unlike their adult counterparts, express this molecule for at least 28 days. Engagement of PD1 by one of its ligands, PDL1, effectively decreases TCR-mediated responses (TNF-α production and degranulation) by neonatal Vδ2 cells and may thus act as a rheostat for this cell subset. We hypothesize that sustained PD1 expression by fetal Vδ2 cells is part of a functional program aimed at controlling inflammatory responses during fetal life. Based on our in vitro data, it is likely that fetal Vδ2 lymphocytes, upon stimulation by microbial antigens, would up-regulate PD1 for a prolonged period of time in vivo as well, thus ensuring that their responses are dampened and controlled. Consistent with our hypothesis, several cord blood specimens collected in Malawi contain at least 20% of PD1+ Vδ2 cells ex vivo. We believe that PD1 expression at birth (induced by prenatal exposure to antigens) may be associated with reduced neonatal Vδ2 cell functions, in particular cytotoxicity, because we reproducibly observed that PD1+CD56- Vδ2 lymphocytes after expansion display less cytotoxic mediators and lower degranulation compared to PD1-CD56+ cells. The effects of PD1 expression on fetal Vδ2 cell responses most likely depend upon the PDL1 levels present in the microenvironment, and may range from modest inhibition of cytokine production (in presence of low PDL1 levels) to induction of apoptosis and deletion of the most activated cell clones (in highly inflammatory environments that induce robust PDL1 up-regulation). Regardless, either deletion of activated clones or persistence of PD1 on Vδ2 lymphocytes after birth may attenuate their responses to pathogens in early life, when they are likely needed the most.