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Innate versus Adaptive Immunity: A Paradigm Past Its Prime?

Department of Immunology, University of Pittsburgh Department School of Medicine, Pittsburgh, Pennsylvania

Requests for reprints: Lisa Borghesi, Department of Immunology, University of Pittsburgh Department School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261. Phone: 412-383-7074; Fax: 412-383-8098; E-mail: borghesi{at}pitt.edu.

	Abstract

Top Abstract Introduction Characteristics of the... Candidate Bridge Populations The Immune Response as... Future Directions References

 
Studies in tumor immunology have relied upon the classic paradigm of distinct innate and adaptive parts of the immune system. However, recent advances in immunology suggest that this division may be overly simplistic, with emerging evidence of a breakdown in conventional hallmarks of each system. Here, we provide an overview of this area and discuss how the concept of a continuum of immune cell populations suggests novel areas of investigation in cancer research. [Cancer Res 2007;67(9):3989–93]

	Introduction

Top Abstract Introduction Characteristics of the... Candidate Bridge Populations The Immune Response as... Future Directions References

 
Classically, the innate and adaptive arms of the immune response have been represented as two separate systems with distinct properties. The innate immune system is widely recognized to use a small number of germ line–encoded receptors that detect a limited set of conserved antigens. This system responds to antigens with fast kinetics and it lacks memory capabilities. In contrast, the adaptive immune system uses a large number of variable immune receptors to generate a vast repertoire. This system responds with relatively delayed kinetics and it possesses effective recall responses (Box I). Recently, several studies have described hematopoietic cells bearing the hallmark characteristics of both the innate and adaptive immune systems. Thus, it is becoming unclear how to classify the increasing number of hematopoietic populations that do not neatly fit within this binary scheme.

At present, there are seven major populations that do not conform to conventional bimodal criteria: natural killer T (NKT) cells, T cells, CD8 T cells, B1 B cells, marginal zone (MZ) B cells, and subsets of both NK cells and neutrophils. As detailed below, these lymphocyte subsets are recognized to possess seminal properties of both the innate and adaptive responses. One consequence is that B1 B lymphocytes, for example, are alternately referred to as either innate cells (1–3) or innate-like cells (4–6). Yet, B1 B cells fail to develop in rag-deficient or severe combined immunodeficient (SCID) mice, a hallmark criterion of adaptive immunity. So which classification of these cells is more accurate, innate, innate-like, or adaptive? Similarly, invariant NKT cells and T-cell subsets are alternately grouped with innate or adaptive responses depending on the criteria emphasized (1, 3, 7, 8). As with B1 B cells, neither invariant NKT cells nor T cells develop in the absence of rag gene expression. Importantly, all these interpretations are scientifically justified because the developmental and functional properties blend key innate and adaptive characteristics. Thus, the lack of consensus stems not from promiscuous use of terminology but from an inability of the current framework to accommodate these populations in a biologically meaningful way. Recently, NK cells and neutrophils have been found to possess both memory and variable immune receptors, which have been thought to be specific features of adaptive immune cells. The findings and implications of these provocative studies (9, 10) have yet to be fully appreciated by the scientific community. Below, we review the data underlying all of these newly described cells and provide a perspective.

	Characteristics of the Conventional versus Nonconventional Hematopoietic Populations

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Antigenic specificity. Receptors of the innate versus adaptive immune system are also distinguished by the nature and composition of the antigens to which they will react. Innate immune receptors commonly recognize a limited number of target molecules, including lipopolysaccharide, phosphoantigens, lipids, and double-stranded RNA, that are widely expressed by many infectious agents. Adaptive immune receptors recognize complex proteins that can be widely shared or uniquely expressed by individual pathogens. In contrast to innate immune receptors for which ligands seem to be highly conserved, receptors of the adaptive immune system detect both conserved and non-conserved ligands. Although the ligands for innate versus adaptive immune receptors differ, it is important to realize that recognition of a restricted array of antigens does not necessarily imply a lack of specificity in the innate immune system (16), rather the fundamental difference in the innate immune system is in the nature of the antigens it recognizes.

What types of antigens are recognized by non-conventional cells, also termed bridge cells? In the case of B1 B cells, sugar and lipid antigens are recognized. Indeed, 5% to 8% of the B1 repertoire in the murine peritoneal cavity reacts to phosphorylcholine (14). These patterns contrast with the recognition specificities of ß T cells and B2 B cells, which are largely, but not exclusively, characterized by peptide epitopes. Alternately, classic NKT cells are defined by CD1-restricted recognition of GalCer, a mimic of microbial cell wall glycuronosylceramides, as well as other bacterial products. GalCer-responsive NKT cells mediate effective antitumor responses in murine models of fibrosarcoma as well as carcinomas of the colon, breast, or lung (17). The immunotherapeutic potential of these cells was recently highlighted by a phase I trial in which autologous NKT cells expanded with GalCer and interleukin 2 were shown to be well tolerated by patients with advanced non–small-cell lung cancer (18). In contrast to ß T cells, T cells do not require binding and presentation by classic MHC. Rather, a high proportion of human circulating T cells recognize small phosphorylated molecules of mycobacterial origin, including organic phosphates and alkylamines. Treatment of human tumor cells with therapeutic drugs containing aminobiphosphonates generates a novel antigen structure that stimulates human T cells, suggesting a new strategy for cancer immunotherapy (19). Human T cells have been shown to prevent or inhibit the growth of breast cancer cell lines in vitro (20) and autologous melanoma in a human tumor/SCID model in vivo. The distinct in vivo trafficking patterns of V1 versus V2 T cells may be useful for targeting specific tumor types (21, 22). The recognition of the distinct reactivities of bridge populations combined with their role in cancer immunosurveillance offers the tremendous potential for novel disease therapies.

Response kinetics. Cells of the innate immune system respond quickly, in minutes to hours, after microbial infection. By contrast, adaptive immunity offers a highly tailored response delivered at the expense of delayed kinetics, which can be on the order of weeks to peak responsiveness. Like innate immune cells, both B1 B and MZ B cells respond rapidly to limit bacterial spread during invasion, with a peak of IgM production occurring 3 to 4 days after antigen encounter. Like conventional B2 cells, the activity of the Blimp-1 transcriptional repressor is also required in B1 B cells despite the different kinetics of responsiveness of these two lineages (6). In a model of Listeria infection, T cells can also respond rapidly to infection, with peak expansion at 10 days following infection (23). Both CD8 T cells and NKT cells are activated and produce IFN within hours after activation. Thus, the combination of rapid response kinetics and patterns of specific reactivity to microbial antigens enables these lymphocyte populations to bridge the temporal gap between innate and adaptive responses.

Clonal selection. Another hallmark of the adaptive response is the clonal distribution of unique immune receptors. The expression of a single type of immune receptor by an individual lymphocyte enables clonal selection of each cell based on the affinity of that receptor for its ligand. Hence, a small number of specific naive cells expand in response to particular antigenic epitopes. One consequence of clonal selection is that the ß T-cell and B2 B repertoires of the adaptive immune system are unique to each individual. By contrast, germ line–encoded receptors within the innate immune system can be restricted to specific subsets, but they are not clonally distributed. Thus, groups of individuals within a particular species may share an identical receptor repertoire (16). Consistent with the adaptive immune system, NKT cells, T cells, CD8 T cells, B1 B cells, and MZ B cells each express a single type of immune receptor. The specific negative and positive selection mechanisms that control entry of these cells into the mature pool remains an active area of investigation.

	Candidate Bridge Populations

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Memory NK cells? A conventional hallmark of the innate immune system is the absence of memory. Thus, repeated exposure to the same antigen does not lead to a qualitative or quantitative enhancement in the ensuing response. Unexpectedly, murine NK cells have recently been shown to have memory-like activity (9). Using a murine model of contact dermatitis, NK cells were shown to mediate hapten-specific memory responses up to 4 weeks after initial challenge. Contact sensitivity responses were detectable at comparable magnitude in rag-deficient animals, showing the B and T independence of this response. By contrast, depletion of NK cells in any of three experimental models, rag2^–/–c^–/–, SCID x beige, or rag2^–/– + anti-asialo-GM1 treatment, abrogated this memory response. The ability of NK cells to infiltrate sensitized tissue was specific to re-challenge with the original hapten. It remains unclear how long the initiating hapten persists in vivo and whether the primary response is fully subsided before re-challenge (3). Moreover, memory responses of NK cells seem to be strongly influenced both by mouse strain and the specific sensitizing hapten. Although the generality of these observations remains to be established, the description of these NK cells as "adaptable innate killers" (3) or "adaptive killers" (24) highlights the importance and the challenge of accurately characterizing these cells within the existing innate versus adaptive framework.

The memory capabilities of bridge lymphocytes are just beginning to be appreciated. B1 B lymphocytes are a lymphoid population also originally thought to lack memory. In a murine model of spirochete infection, IgM-producing B1b cells were shown to provide protective immunity as long as 80 days after the initial challenge (25). This result was unexpected because T-cell–independent responses do not generally elicit B-cell memory. By comparison, T cells do not seem to make a major contribution to the memory pool. Although exceptions exist (26), the majority of effective recall responses seem to be due to ß T-cell activity. Little is known about the memory capabilities of NKT cells as secondary responses to GalCer seem to be of lesser magnitude than primary responses. However, this effect may be due to the anergizing effects of GalCer.

Neutrophils and variable immune receptors? One recent study has suggested the novel hypothesis that a small subset of neutrophils express variable immune receptors that are the product of V(D)J recombination (10). Neutrophils are major proinflammatory mediators that are among the earliest innate effectors recruited to sites of injury and infection. The idea that cells of the innate immune system bear V(D)J rearrangements is not new. Both NK cells and pDCs harbor incomplete rearrangements at immunoglobulin and TCR loci (27). These observations are not surprising given the common lymphoid origins of B, T, NK, and dendritic cells, and that V(D)J rearrangement initiated at the uncommitted progenitor stage of development would be detectable in downstream progeny (27, 28). What is surprising is the reported detection of complete TCR ß rearrangements in a small population (5–8%) of neutrophils, which are cells of the myeloid lineage (10). These rearranged TCRs are thought to signal through a CD3/CD28 mechanism. TCR⁺ neutrophils are detectable in nude mice, animals that lack conventional T and NKT cells, suggesting that these results could not be attributed to the presence of conventional TCR⁺ lymphocytes. However, nude mice still possess T cells of extrathymic origin, and it will be important to exclude this potential contaminating population in future experiments. It will also be informative to explicitly determine the effects of rag deletion on the development and function of neutrophils.

	The Immune Response as a Continuum

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The overview of the major lineages of hematopoietic cells provided above illustrates clearly that not all immune cells can be assigned strictly to either the innate or the adaptive arm of the immune system. Little doubt exists about the important biological roles of NKT cells, T cells, CD8 T cells, B1 B cells, and MZ B cells, or that these subsets possess key features of both innate and adaptive immunity. The existence of bridge populations between the two classic subgroups of immune cells prompts a need to expand the paradigm of innate versus adaptive immunity. Revising our perspective on the immune system as an organizational continuum, rather than a dichotomy, acknowledges the bridge population subsets that have functional properties drawn from the innate and adaptive end points. Additionally, it allows one to integrate the concept of the bridge populations of immune cells with a unified terminology (Table 1 ).

	Future Directions

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Reorganizing the immune system as a continuum rather than a dichotomy makes at least three interesting predictions. One prediction is that bridge populations may offer excellent targets for vaccine therapy. Rather than providing an impoverished immune response whose activity is elicited in lieu of adaptive immunity, bridge populations may orchestrate entirely distinct patterns of immune responsiveness. T cells neutralize a number of pathogens, including Klebsiella pneumoniae, for which ß T cells are dispensable (31). Likewise, B1a and MZ B cells mount antibody responses in the absence of T cells. Vaccine strategies that target bridge populations may be useful for some situations in which current vaccines fail, such as those that are exclusively targeted to Th-dependent B2 B cells. Such strategies may have particular value for situations in which T-cell activity can be associated with fatal encephalitis, such as in the treatment of cancers of the brain or the therapeutic destruction of amyloid plaques in Alzheimer's patients (32). The identification of a specific subset of dendritic cells that uniquely captures and transports blood-borne antigens to MZ and B1 B cells suggests one mechanism of targeted delivery (33). A second prediction based on the gaps in the continuum is that additional bridge populations will be identified. Notably absent is a bridge population derived from the macrophage lineage. Not only do macrophages and B lymphocytes share key functional properties, such as phagocytic capacity, but they can arise via a bi-potent macrophage/B-cell precursor (34). Whether these unusual bi-potent precursors give rise to functional, mature progeny that retain the characteristics of both lineages remains unknown. The occurrence of leukemias that express traits of both lineages may be one hint that such cells exist (35). A third prediction is that some instances of autoimmunity may be attributable to the activity of bridge populations. The tendency of B1 B cells to produce autoreactive antibodies has not gone unnoticed but the feedback mechanisms that restrain these cells as well as other bridge populations remain largely unexplored. Each of these predictions is a testable hypothesis that affects our basic understanding of the functional organization of the immune system.

Observations that V(D)J rearrangements are detectable not only in B and T cells but also in a minor population of NK, pDC, and possibly neutrophils suggest that rag-mediated DNA translocation may be an unappreciated source of oncogenesis in multiple hematopoietic lineages. As 50% of CLPs express rag1/2 transcripts (36), it is also possible that recombination errors at this stage cause transformation. rag complex misrecognition caused by a pseudo-recombination signal sequence or a fragile breakpoint can lead to rearrangements between antigen receptor loci and bcl2, LMO2, Tgt-1, or SIL (37). Other common chromosomal partners include cyclin D1, cyclin D3, FGFR3, and MMSET gene loci, all of which lead to unrestricted cell growth (38). NK and NK-like tumors have been identified (39–41), but they remain a perplexing problem because their lineage origins are controversial. Moreover, the molecular changes that lead to transformation of NK cells are unclear, and translocations can be heterogeneous. Similarly, cancers of neutrophilic origin, such as chronic neutrophil lymphoma, require better criteria for diagnosis and identification of the underlying molecular defects including chromosomal abnormality (42). The current appreciation of recombination events in a subpopulation of NK cells and other hematopoietic lineages may aid in clarifying disease definitions and malignancy types.

	Acknowledgments

 
Grant support: American Heart Association (L. Borghesi), Elsa U. Pardee Foundation (L. Borghesi), U.S. Immune Deficiency Network (L. Borghesi), and NIH grant R01CA086433 (C. Milcarek).

We thank Olja Finn, Ken Dorshkind, Bill Chambers, and Jay Kolls for insightful comments.

Received 1/17/07. Revised 3/ 2/07. Accepted 3/ 6/07.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Borghesi, L. Articles by Milcarek, C. Search for Related Content PubMed PubMed Citation Articles by Borghesi, L. Articles by Milcarek, C. Related Collections Cancer Immunology Cancer Immunology: Innate Immunity Cancer Immunology: Adaptive Immunity