Lymphoid Ontogeny Research Articles

4 - Immunology of the Fetus and Newborn: Lymphocyte Phenotype and Function

Lymphocyte development begins early in the first trimester of gestation, and the fetus is capable of normal cytotoxic responses and some degree of T-B cooperation early in the second trimester. Neonates, however, are not fully immunocompetent at birth. They produce a restricted library of immunoglobulin isotypes and experience a ‘physiological hypogamma-globulinaemia’ for weeks or months. Premature infants are more profoundly hypogammaglobulinaemic for a longer time, and are less able to mount an appropriate response to bacterial or viral challenge, than term infants. Phenotypic analysis of lymphocyte populations from umbilical cord blood shows that lymphoid ontogeny is reflected in changing lymphoid subpopulations in peripheral blood of neonates throughout the third trimester of gestation. Immaturities exist in both B and T cell subsets in cord blood. These irregularities are most marked in early third trimester. Moreover, certain types of severe antenatal stress may alter the normal temporal sequence of acquisition of T and B lymphocyte surface antigens. The presence of T6+ cells in some cords suggests the possibility that profound stress, which causes the thymus to shrink, may also cause thymocytes to be released into circulation before the normal sequence of maturation is complete. These lymphocytes may be analogous to the ‘leftward shifted’ neutrophil band forms which are released into circulation in response to bacterial infection. Finally, newborns in general, and severely stressed or very premature newborns in particular, are at increased risk from infection not only because their immune systems are inexperienced, but primarily because their circulating T and B lymphocytes are at a stage of differentiation which may not permit them to function effectively in response to antigenic challenge.

BALB- and Harvey-murine sarcoma virus transformation of a novel lymphoid progenitor cell.

BALB- and Harvey-murine sarcoma viruses (MSV) comprise a family of retroviruses whose mouse- and rat-derived onc genes are closely related. These viruses induce sarcomas and erythroleukemias in susceptible animals. An in vitro colony assay that detects transformation of lymphoid cells by Abelson-murine leukemia virus was used to demonstrate that BALB- and Harvey-MSV transform a novel hematopoietic cell both in culture and in vivo. Bone marrow colony formation was sarcoma virus dependent, followed single-hit kinetics, and required the presence of mercaptoethanol in the agar medium. BALB- and Harvey-MSV-induced colonies could be established in culture as continuous cell lines that demonstrated unrestricted self-renewal capacity and leukemogenicity in vivo. The cells had a blast cell morphology and lacked detectable markers of mature cells within the myeloid or erythroid series. They also lacked detectable immunoglobulin mu chain or Thy-1 antigen, markers normally associated with committed cells of the B and T lymphoid lineages, respectively. However, the transformants contained very high levels of terminal deoxynucleotidyl transferase (TdT), an enzyme believed to be specific to early stages within the lymphoid differentiation pathway. This phenotype distinguishes these BALB- and Harvey-MSV transformants from any previously reported hematopoietic targets of transforming retroviruses, including the pre-B lymphoid cell transformed by Abelson-MuLV under identical assay conditions. These newly identified lymphoid progenitor cell transformants may provide an important means of studying early stages of lymphoid ontogeny and the possible role of TdT in lymphoid development.