A hallmark of adaptive immunity is the generation of long-lived, antigen-specific memory T, B, and NK lymphocytes that mount strong anamnestic (recall) responses to previously encountered antigens. However, it is not known whether innate myeloid cells are also capable of generating anamnestic responses with properties similar to those of lymphoid cells. To test this possibility, we studied the monocyte response to allogeneic non-self. We immunized B6 gamma-chain/RAG knockout (gc/RAG KO) mice, which lack all lymphoid cells, with irradiated B6, BALB/c or C3H splenocytes i.p. and re-challenged them 1, 4, and 7 wks later with BALB/c bone marrow (BM) plugs transplanted under the kidney capsule. The number of mature, monocyte-derived host dendritic cells (mono-DC) present in the BM grafts was quantitated 7 days after transplantation. We observed that mice immunized with BALB/c (allo) splenocytes generated 5- and 3-fold more mono-DC than those immunized with either B6 (syn) or C3H (3rd party) splenocytes at 1 and 4 wks after immunization, respectively. The exaggerated monocyte response returned to baseline at 7 wks. Conversely, immunization with C3H but not BALB/c splenocytes amplified the host monocyte response to C3H BM grafts, confirming the specificity of the recall response. A recall alloresponse could be elicited in naive gc/RAG KO recipients after adoptive transfer of sorted monocytes from allo- but not syn-immunized gc/RAG KO mice, establishing that monocytes are indeed responsible for the memory response. Finally, the potential contribution of lymphoid cells present in either the immunogen (irradiated splenocytes) or the BM graft to the host monocyte memory response was ruled out by duplicating our initial findings using B6, BALB/c and NOD (as 3rd party) donors that are all on the gc/RAG KO background. These results provide direct evidence for specific innate immune memory to allogeneic non-self that is moderately long-lived and is mediated by monocytes independently of lymphoid cells. The findings have important implications for understanding how innate immune mechanisms contribute to rejection and interfere with transplantation tolerance.

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