Recently, the distinctions between innate and adaptive immunity have become blurred. Certain subsets of B and T cells, suchas B1 cells, γδ T cells, and invariant natural killer T (iNKT) cells, are often referred to as innate-like lymphocytes 1
. The phenotype of such innate-like lymphocytes in naïve animals is often more similar to that of effector cells than of small, resting lymphocytes that have not previously encountered an antigen or pathogen. This is reflected by their constitutive expression of certain activation or memory cell surface markers, and by their ability to mediate effector functions, such as cytolytic activity or cytokine production, rapidly after stimulation through their antigen receptors. The antigen receptor repertoire of these innate-like lymphocytes, including iNKT cells and some subsets of γδ T cells, might also be more restricted than that of conventional T cells.
Reciprocally, certain innate immune cells also seem not to fit the conventions. Recent studies have shown that natural killer (NK) cells, which are considered to be lymphocytes of the innate immune system, have several features that are normally attributed exclusively to cells of the adaptive immune system 2, 3
. Mouse NK cells that express the germline-encoded, invariant receptor Ly49H, which specifically recognizes the m157 glycoprotein encoded by cytomegalovirus (CMV) 4
, clonally expand during viral infection and the population then contracts after control of the infection 5
. Surprisingly, a subset of these CMV-specific NK cells can persist in the host for months after infection and can demonstrate a “recall” response, resulting in the marked clonal expansion of cells that are specific for m157 after a second exposure to CMV 3
. Although these “memory” NK cells proliferate with similar kinetics to naïve NK cells after infection, they have a more robust cytolytic and cytokine response, and protect the host more efficiently than naïve NK cells. Therefore, the fundamental behaviour of conventional CD8+
T cells and NK cells during CMV infection is remarkably similar. One significant difference, however, is that before immunization, CD8+
T cells specific for any particular antigenic determinant are present at exceedingly low precursor frequencies in naïve hosts (typically estimated at ≤1 in 100,000 T cells), whereas the CMV-specific Ly49H+
NK cells are present at high precursor frequencies (comprising about 50% of NK cells in C57BL/6 mice) before infection.
What are the distinguishing features of memory cells? First, memory implies that an antigen-activated cell or its clonal progeny can survive for a relatively long time after the pathogen or antigen has been cleared from the host. These cells must then be able to respond to re-exposure to the same antigen or pathogen in a qualitatively different manner than naïve cells. The recall response can be reflected by faster proliferation or more robust effector functions, such as secreting higher levels of cytokines and chemokines or producing them more quickly, or in the case of cytotoxic cells, as being able to kill target cells sooner or more efficiently after a second encounter with the specific antigen or pathogen. Although it is generally assumed that memory T cells proliferate faster than naïve T cells after antigen-specific stimulation, studies in T cell receptor(TCR)-transgenic mouse models have shown that, at least for certain T cells, the kinetics of proliferation are essentially identical for naïve and memory T cells 6
, with the difference in the response being largely accounted for by a higher frequency of memory than naïve T cells specific for a particular antigen. With respect to effector functions, memory T cells are more efficient at mediating cytokine production and cytotoxicity after TCR ligation than naïve T cells. Prior studies have documented qualitative differences between naïve, effector and memory T cells using transcriptional profiling techniques 7
When considering the role of memory cells in an immune response, one typically thinks of their actions after they are re-challenged with the same pathogen or antigen. The vigorous clonal expansion of memory B or T cells is indeed antigen specific; however, an underappreciated aspect of memory cells is that they can also be activated and contribute to immune responses in a non-antigen-specific manner. For example, memoryB cells can proliferate and secrete antibody when stimulated by CpG-containing DNA (through Toll-like receptor 9, TLR9) and interleukin-15 (IL-15), without requiring cognate antigen, whereas naïve B cells are unresponsive to CpG DNA and IL-15 in the absence of antigen 8
. Similarly, unlike naïve T cells, memory T cells can secrete interferon-γ (IFNγ) in a non-antigen-specific manner. During bacterial infection, memory T cells, but not naïve T cells, rapidly secrete IFNγ in response to IL-12 and IL-18 produced by dendritic cells, in the absence of cognate antigen 9, 10
. Moreover, when mice are injected with poly I:C (which induces the production of type I IFN by stimulation of plasmacytoid dendritic cells through TLR9) or endotoxin (which stimulates myeloid cells through TLR4 to produce IL-12 and IL-18), memory T cells, but not naïve T cells, secrete IFNγ in the absence of cognate antigen 11, 12
Similar to memory T cells, the ability of “memory” Ly49H+ NK cells to undergo clonal expansion is strictly antigen specific in that re-challenge with CMV lacking m157 fails to drive proliferation. However, like memory T cells and memory B cells, when “memory” NK cells are stimulated through other non-antigen-specific receptors, they produce more cytokines than naïve NK cells. Therefore, the “wiring” of memory cells inthe B cell, T cell, and NK cell lineages is different than in naïve cells, allowing the memory cells to participate in an immune response not only against the cognate antigen previously encountered, but also against other infections in a bystander manner. This ability of memory cells to non-specifically participate during subsequent infection provides chemokines and cytokines such as IFNγ very rapidly to activate local dendritic cells, macrophages, and granulocytes and might help to recruit and augment the differentiation of naïve antigen-specific cells.
The recent studies uncovering the existence of “memory” NK cells should prompt a re-evaluation of other innate immune cells. Certain populations of myeloid cells, for example Langerhans cells have been shown to be long-lived in mice 13
. After myeloid cells are initially stimulated through their TLRs, how long does this activation state last? Do these myeloid cells “adapt”, acquiring a long-lived alteration in their kinetics of response or transcriptional signature when they are stimulated at a later time, either through the same receptors or receptors not involved in the previous immune response? Phagocytic cells in Drosophila melanogaster
apparently can “remember” prior infections, having specificity for some bacteria but not others 14
. There is evidence for an enhanced immune response against microbial pathogens upon a second encounter in several invertebrates, including water fleas, copepods, red flour beetles, bumble-bees, and cockroaches, and an elevated second-set rejection of allogeneic colonies has been demonstrated in tunicates, sea urchins, and sponges 15
. Therefore, the ability of the immune system to behave differently on a second encounter with the same pathogen or allogeneic organism appears to pre-date the evolution of cells with the ability to generate antigen-specific receptors by somatic gene recombination.
In the end, what distinguishes “innate” and “adaptive” immunity? Is a qualitatively distinct response of an immune cell after a second stimulation sufficient to consider it “adaptive”? How long after the clearance of a pathogen or antigen do the responding immune cells need to persist and display a qualitatively distinct response to re-challenge to be considered “memory” cells? If the definition of adaptive immunity is that the cells require productive somatic gene rearrangement of their primary receptor for antigen whereas innate immune cells solely rely on invariant, germline-encoded receptors for sensing pathogens, then the distinction between innate and adaptive immunity is unambiguous. However, when antigen-specific B cells and memory T cells mediate non-antigen-specific responses, often using innate-like receptors, and when “innate” immune cells display many of the hallmarks of “adaptive” immune cells – a strict binary classification becomes rather meaningless. Rather than argue semantics, it is more important to understand these processes and learn to harness them for more efficient control of infectious disease, possibly providing new strategies for vaccination.