Evolved challenges to the innate/adaptive immunity dichotomy

Immunologists routinely distinguish between “innate” and “adaptive” immune responses and mechanisms (Medzhitov, 2008).  It is often the case that the precise criteria underlying this dichotomy are not explicitly cited when the distinction is invoked, but there are several recurring themes.  Innate responses are said to occur over relatively short time intervals, to be less discriminating among antigens, to lack involvement of receptors that are created through gene rearrangement and that are clonally distributed, and to lack memory.  In contrast, adaptive responses are said to occur over relatively long time intervals, to be more discriminating among antigens, to involve receptors that are created through gene rearrangement and that are clonally distributed, and to exhibit memory.

It is often implicitly assumed that for any response, mechanism, cell, or molecule of interest that all of these criteria will segregate in unison.  Little attention is usually devoted to the possibility that a particular response, mechanism, cell, or molecule will offer an uncomfortably mixed pattern of attributes.  For example, the system of serum proteins known as complement is often regarded as participating in innate immunity (Parham, 2005) even though the classical pathway of complement activation relies on triggering by antibodies, which are universally recognized as prototypical components of adaptive immunity.  Furthermore, some complement receptors are expressed by B lymphocytes, the producers of antibodies and one of the two cell types most closely identified with adaptive immune responses.

It is in this context that a recent report (Sun et al., 2009) on anti-viral immunity mediated by murine natural killer (NK) cells is of interest.  Prior work by O’Leary et al. (2006) had already suggested the possibility that NK cells exhibit some measure of immunological memory.  The recent paper by Sun and colleagues offers additional evidence that NK cells, typically regarded as contributing to innate immunity, pose a challenge to those heavily committed to the standard ontology pertaining to innate versus adaptive immunity.  Sun et al. find that murine NK cells expressing a receptor (Ly49H) involved in mediating immunity to mouse cytomegalovirus, or MCMV, exhibit population expansion and contraction phases after exposure to the virus, much like T or B lymphocytes, the chief cellular agents of adaptive immunity.  The authors also provide strong evidence that these Ly49H⁺ NK cells exhibit an enhanced ability to mediate immunity to MCMV following prior infection, or in other words, these NK cells appear to possess what could reasonably be regarded as immunological memory, long identified as one of the hallmarks of adaptive immunity.

Thus, NK cells seem to possess some attributes (e.g., activity without priming, more limited range of antigens recognized than for B or T cells) dictating association with innate immunity and to possess other attributes (e.g., population size increases and decreases following exposure to relevant stimuli, functionally meaningful memory) dictating association with adaptive immunity.  The simple dichotomy between innate and adaptive mechanisms and components does not offer a satisfying means to handle such complexity.

This basic pattern of new findings obliterating a pre-existing correlation among attributes routinely relied upon for classifying entities as members of some biologically relevant category is recurrent.  It is a deep reflection of the evolutionary origins of these processes or structures (Greenspan 2007).  What is curious is that many biologists and biomedical scientists continue to approach classification of responses, mechanisms, cells, or molecules in an essentially pre-Darwinian manner, assuming that categories with inflexible membership criteria will suffice.  As one of innumerable possible examples of the inadequacy of such an approach to biological classification, close inspection of the boundary between innate and adaptive immune mechanisms reveals challenges to the received wisdom that grow in rough proportion to the diligence with which the issue is studied.

References

Medzhitov, R. (2008). The intersection of innate and adaptive immunity. In: Fundamental immunology, sixth edition, Edited by Wm. Paul, Philadelphia, Wolters Kluwer/Lippincott Williams and Wilkins.

Parham, P. (2005). The immune system, second edition. New York, Garland Science.

Sun, J. C., Beilke, J. N., & Lanier, L. L. (2009). Adaptive immune features of natural killer cells. (2009) Nature, 457, 557-561.

O’Leary, J. G., Goodarzi, M., Drayton, D. L., & von Andrian, U. H. (2006). T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nature Immunol., 7(5):507-516.

Greenspan, N.S. (2007). Conceptualizing immune responsiveness. Nature Immunol., 8(1):5-7.