4 Effect of Thymic Hormones on Human Lymphocytes

Abstract

Several peptides have been isolated from thymic tissues and found to circulate in peripheral blood, establishing the role of the thymus as an endocrine gland. These peptides possess the ability to induce differentiation of T cell precursors into more mature T lymphocytes. Evidence of maturation was established by the demonstration of appearance of T cell surface markers (HTLA, E rosette receptors, T cell antigen detected by the monoclonal antibody anti-Leu-2a) on marrow or peripheral blood cells that did not bear these markers originally. On the other hand, PNA receptors and enzymatic activity of TdT were lost after incubation of immature T cell populations with such peptides. Marked enhancement of T cell functions, demonstrated by responses to phytomitogens or allogeneic cells in MLR, was also observed after exposure to thymic peptides. Thus, as T cell precursors differentiate into T lymphocytes, they lose their markers of immaturity and acquire the surface phenotype and the functional activities characteristic of mature peripheral T cells. Acquisition of T cell specificities by marrow cells were shown to require RNA and protein synthesis. In contrast to marrow precursors, the majority of inducible PBLs were not affected by RNA or protein synthesis inhibitors. Less than one per cent of them were found to require protein synthesis. These findings indicate that T cell precursors in marrow are at an earlier stage of differentiation than those in peripheral blood. Evaluation of T cell differentiation in patients with immunodeficiency diseases and leukaemia revealed marked heterogeneity in the response of their marrow or peripheral blood cells in vitro to thymic extracts, peptides or thymic epithelium. In patients with SCID, abnormalities ranging from a complete absence of definable T cell precursors to partial differentiation resulting in the acquisition of the HTLA, or HTLA and E rosette markers were observed. In no case could significant responses to mitogens be elicited. However, following successful transplantation of fetal liver plus thymus, or of bone marrow from HLA-matched sibling donors, marrow cells from these patients acquired the full range of thymic hormone-inducible characteristics. In contrast to SCID patients, those with the DiGeorge syndrome, ataxia telangiectasia, CVI or Wiskott—Aldrich syndrome were found to possess T cell precursors that could respond to thymic hormones in vitro. Furthermore, the study of marrow cells from immunodeficient patients revealed several stages of T lymphocyte differentiation. Cells developing the HTLA phenotype are believed to be the precursors of those that acquire the E rosette receptors, and the latter can differentiate into cells responding to the phytomitogens conA or PHA, or to alloantigens. Similar investigations in vitro were performed before and after treatment of patients with thymic hormones. The results suggest that expression of T cell surface markers as well as functions, such as help, suppression or NK activity, can be induced in vivo. In conclusion, based upon the accumulation of data obtained in vitro on normal and pathological materials, it seems likely that thymic hormones can provide some of the signals necessary for T lymphocyte maturation and should, therefore, have therapeutic application in the future.