The aging immune response is characterized by a compromised effector but intact memory response

Xupeng Ge¹, Anke Jurisch¹, Xiaodong Yuan¹, Bernhard Floerchinger¹, Marc-Olivier Timsit¹, Ying-Lung Lee¹, Stefan G. Tullius¹

¹Division of Transplant Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

The characterization of age-dependent immune responses is gaining clinical significance. Chronological aging has been associated with an accumulation of memory T-cells, however, their function may be incapacitated. We postulated that allospecific memory T-cell responses are age-dependent.

Young (3mth) and old (18mth) C57Bl/6 recipients were sensitized with DBA2/J skin grafts. 4 wks later, memory T cells counts (CD44high and CD62low) had increased in both old and young sensitized mice. Subsequently, DBA2/J cardiac allografts were transplanted into young and old sensitized C57Bl/6 mice.  In the absence of sensitization, the tempo of cardiac rejection was recipient age-dependent and significantly delayed in old compared to young non-sensitized recipients (6.8±0.7 vs 10.0±1.3 days, p<0.0001). Sensitization accelerated rejection in an age-independent way. The temp of rejection was comparable in young and old sensitized recipients (4.9±0.1 vs 5.6±0.6 days, P=ns.). Alloreactivity (IFN-g production) and proliferative capacity (CFSE assay) were comparable in both sensitized old and young recipients.  Adoptive transfer of CD3+ T cells isolated from either young or old sensitized animals into RAG1 knockout recipients results in rejection of DBA skin grafts by 11 days in both groups, indicating an age independent memory T cell function in vivo. Next, we separated memory and naive T-cells by CD-62L beads and evaluated their function. Prior to sensitization, the IFN-g production of CD-62L- memory T-cells was compromised in both young and old animals indicating that the primary alloresponse is driven by naïve T-cells. However, following sensitization alloresponsiveness was mediated predominantly by the memory T-cell population (> 5 fold of increase in both young and old mice). Of note, the memory T-cell response demonstrated an age independent potency and the function of old allospecific memory T-cells following sensitization had been very well preserved.

Increasing recipient age delays the tempo of acute rejection and is associated with a compromised primary T-cell response. Sensitization accelerates rejection in an age-independent fashion associated with a potent and well preserved alloresponsiveness of older memory T-cells. Those data have important clinical implications on age-adapted immunosuppression.