Discovery and characteristics of endowed immunity
Dai et al. 46 showed that mice monocytes/macrophages
can acquire an alloantigen-specific memory in response to secondary
encounters, and identified that paired immunoglobulin-like receptor-A
(PIR-A), a major histocompatibility complex (MHC)-I receptor, was
necessary for the induction of macrophage memory. Either deleting PIR-A
or blocking the PIR-A-MHC-I combination was demonstrated to suppress
memory and attenuate the allograft rejection in kidney and heart
transplantation. Similarly, Liu et al. 47 have
reported that during secondary challenge, macrophages have the capacity
to recognize and reject allogeneic antigens, which requires two signals,
namely, priming with allogeneic antigens and the assistance of
CD4+T cells. Chu et al. 48 also
showed that macrophages primed with allogeneic antigens mounted an acute
response to skin allografts with a certain degree of antigen
specificity, which is similar to the characteristics of adaptive immune
cells. The authors demonstrated that immunodeficient recipient mice
showed no signs of rejection to allogeneic skin grafts, which is
consistent with the findings of previous studies that have established
that innate immune cells alone are insufficient to facilitate the
rejection of allogeneic organ grafts. However, they found that
immunodeficient recipient mice, which received antigen-immunized
macrophages (primed macrophages) from immunocompetent mice, were able to
efficiently reject the same allogeneic skin grafts, although not
third-party skin grafts, or showed significantly slower rejections of
the grafts. In summary, when primed macrophages in immunocompetent mice
are exposed to the same allogeneic antigen secondarily, primed
macrophages undergo pronounced proliferation, expand during the immune
response and exert a direct graft-rejection effect, at least partially,
via a perforin-dependent pathway.
In addition, the assistance of helper CD4+T cells, but
not CD8+T cells, during the priming period was found
to be essential for naïve macrophages to gain the ability to distinguish
allografts and thus promote rejection 48-50. In a
follow-up study, the same authors reported that the specific memory of
primed macrophages in the rejection of allogeneic cells and skin grafts
was long-term and persisted for at least 4 months (until the end of the
experimental period) 51.
In conclusion, macrophages can
become endowed with memory that facilitates the recognition of
allogeneic antigens or specific molecules, and thereby induce an
inflammatory response on secondary encounter. Accordingly, suppressing
this memory may represent a potential therapeutic strategy for improving
transplantation outcomes. However, in a study of mouse alveolar
macrophages, Yao et al. 52 found that the induction of
macrophage memory after respiratory viral infection required the
assistance of effector CD8+ T cells, but not
CD4+ T cells.
Taken together, the findings of the aforementioned studies indicate that
functional endowed immunity may require the assistance of different
types of T cells in different disease models. Hence, further studies are
needed to determine which T cell subsets facilitate the induction of
macrophage memory under different conditions.
Although endowed immunity may be
associated with the secretion of inflammatory effectors and amplified
adaptive immune responses 45, 53, the precise nature
of the underlying molecular mechanisms remain unclear and necessitate
further study.