The amino acid sequence of thymosinj,84, a polypeptide isolated from calf thymus, was determined. Thymosin 184 is composed of 43 amino acid residues and has a molecular weight of 4982 and an isoelectric point of 5.

Thymosin fraction 5, a family of acidic polypeptides isolated from bovine thymus, contains several hormonal-like factors which have been shown to influence the maturation, differentiation and functions of T-cells. Some of these peptides have been chemically defined. Two of them, thymosin alpha 1 (M.W. 3108) and thymosin beta 4 (M.W. 4982) have been sequenced. In murine systems, terminal deoxynucleotidyl transferase (TdT) has been shown to be T-cell specific and to be present primarily in the cortisone sensitive immature T-cell populations. The daily injection of thymosin fraction 5 and two of its components, thymosin beta 3 and beta 4, significantly increases TdT activity in immune suppressed mice as compared to control groups. This study indicates that thymosin can act on prothymocytes and influence the early stages of T-cell differentiation. In an in vivo system, thymosin fraction 5 and the purified peptide, thymosin alpha 1, have high activities in decreasing TdT in normal murine thymocytes after a 22-h incubation. This effect suggests that thymosin can also act on thymocytes and regulate the later biochemical processes during T-cell differentiation.

Thymosin fraction 5 contains several distinct hormonal-like factors which are effective in partially or fully inducing and maintaining immune function. Several of the peptide components of fraction 5 have been purified, sequenced and studied in assay systems designed to measure T-cell differentiation and function. These studied indicate that a number of the purified peptides act on different subpopulations of T-cells (see Figure 1). Thymosin beta 3 and beta 4 peptides act on terminal deoxynucleotidyl transferase (TdT) negative precursor T-cells to induce TdT positive cells. Thymosin alpha 1 induces the formation of functional helper cells and conversion of Lyt- cells to Lyt 1+, 2+, 3+ cells. Thymosin alpha 7 induces the formation of functional suppressor T-cells and also converts Lyt- cells to Lyt 1+, 2+, 3+ cells. These studies have provided further evidence that the thymus secretes a family of distinct peptides which act at various sites of the maturation sequence of T-cells to induce and maintain immune function. Phase I and Phase II clinical studied with thymosin in the treatment of primary immunodeficiency diseases, autoimmune diseases, and cancer point to a major role of the endocrine thymus in the maintenance of immune balance and in the treatment of diseases characterized by thymic malfunction. It is becoming increasingly clear that immunological maturation is a process involving a complex number of steps and that a single factor initiating a single cellular event might not be reflected in any meaningful immune reconstitution unless it is the only peptide lacking. Given the complexity of the maturation sequence of T-cells and the increasing numbers of T-cell subpopulations that are being identified, it would be surprising if a single thymic factor could control all of the steps and populations involved. Rather, it would appear that the control of T-cell maturation and function involves a complex number of thymic-specific factors and other molecules that rigidly control the intermediary steps in the differentiation process.

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