The life history, within the rat, of lymphocytes responsive to histocompatibility isoantigens in the mixed lymphocyte interaction was examined by the use of in vivo labeling with tritiated thymidine and radioautography. Lymphocytes in the peripheral blood and H-ARC (mitotic figures in the MLI) were compared with respect to the frequency of labeled cells and the median grain count. The following conclusions were drawn from this study: (a) Although some can be considered long-lived, the majority of H-ARC are the products of recent divisions in the body. (b) Adult thymectomy does not eliminate the production of long-lived lymphocytes, some of which are H-ARC. Hence, in addition to direct origin in the thymus, H-ARC, as well as other lymphocytes of the long-lived lymphocyte population, may derive from already existing thymus-derived cells in the circulation and thymus-dependent areas of the secondary lymphoid tissues. (c) Sublethal X-irradiation (600 R) in combination with adult thymectomy does not eliminate the capacity to produce some long-lived lymphocytes, however, few if any are H-ARC. (d) H-ARC and other long-lived lymphocytes appear to go through a series of rapid multiple divisions before they enter the circulation. Thereafter, long-lived lymphocytes appear to undergo intermittent single divisions which decrease both the frequency and median grain count of labeled cells gradually with time. On the other hand, labeled H-ARC maintain a more stable grain count despite a rapid decrease in frequency with time. This is taken to indicate that H-ARC are less likely to undergo occasional single divisions during their life-span, but may undergo periodic rapid sequential divisions.

A speculative model is developed from these data on the life history of H-ARC which may be of predictive value in future studies and which can be tested against known facts.

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