Asymmetric Reconstitution of γδ T Cell Subsets after Haemopoietic Stem Cell Transplantation.

Abstract In previous studies we and others have shown that the production of new T cells from the thymus declines after the third decade and that while patients below the age of 30 reconstitute primarily new T cells, those over thirty reconstitute primarily by expansion of pre-existing mature T cells. However little attention has been paid to the γδ subset of T cells, which form an important component of mucosal immune protection and which represent approximately 5% of peripheral T cells. Two major subsets of γδ T cells are defined by the expression of Vδ1 versus Vδ2, with Vδ1+ cells predominating in the fetal circulation and in mucosal sites, while Vδ2+ cells predominate in adult life and in the peripheral circulation. In light of the differerential preponderance of the two subsets in the fetal versus adult circulation, we have examined the reconstitution of these two subsets of γδ T cells following hemopoietic stem cell transplantation in a cohort of 28 patients sampled at 3 monthly intervals to ask whether both subsets recover adequately from adult stem cells. In 44 normal individuals, the median levels of Vδ1 and Vδ2 cells are 12.46 (0.22 to 167.8) and 32.78 (4.48 to 190.1) cells/mm3 respectively. In patients under 30, the reconstitution of the Vδ1 and Vδ2 subsets follow similar kinetics, reaching a plateau at 9 months post transplant with comparable numbers of Vδ1 and Vδ2 cells (note that the normal ratio of Vδ1 to Vδ2 is 0.38, so in the patients there is a significant increase in the proportion of Vδ1 cells in the peripheral circulation). In patients over 30 years of age, there is an even more significant disparity in the reconstitution of the two subsets. The Vδ1 subset recovers with similar kinetics as is seen in the patients under 30, although to slightly lower final levels. The Vδ2 subset, however, shows very little recover y, reaching a plateau at 6 months at the bottom of the normal range for up to 2 years post transplant. In these patients the ratio between Vδ1 and Vδ2 is inverted with an increasingly greater proportion of Vδ1 cells at longer times after transplant, with ratios in excess of 10 by 24 months post transplant, a 30-fold increase in the normal proportion of Vδ1 + T cells. Given that the Vδ1 subset shows a very restricted repertoire compared to the Vδ2 subset, the overall capacity of the circulating γδ T cell population to recognise and respond to antigen will be significantly compromised in older transplant recipients.