A rescue gone wrong

Becoming covered in platelets rescues complement-opsonized blood-borne bacteria from rapid clearance by macrophages and redirects them to dendritic cells. Although this allows priming of T cells and the generation of immune memory, bacteria can exploit this route as a beachhead and disseminate throughout host tissues.

Blood is sterile; however, after injury, surgery or an encounter with contaminated catheters or syringes, bacteria can enter the circulation. Systemic bacterial dissemination via the bloodstream (hematogenous spread) is associated with the pathophysiology of many infectious diseases, such as meningitis and endocarditis. Bacteremia has dire consequences for the host, triggering uncontrolled innate immune responses that cause septic shock, which is associated with notoriously high mortality rates. Rapid and efficient clearance of microbes from the bloodstream is hence absolutely mandatory for host survival. Accordingly, vertebrates have developed a highly efficient clearance mechanism that dooms bacterial intruders to efficient phagocytosis and destruction by macrophages via the deposition of host complement components on their surfaces. As it rapidly restores blood sterility, this hard-wired innate immune defense saves the host. However, mammals can go one better. By recruiting lymphocytes to the response, they can generate immunological memory and thus achieve long-term protection against a potential repetitive pathogen encounter. The initiation of this 'adaptive' immunity, however, does not rely on macrophages. These phagocytes rapidly shred the bacteria and thereby deprive the host of bacterial antigen sufficient to mount an optimal adaptive immune response1. Instead, the initiation of adaptive immunity requires dendritic cells (DCs), which, in contrast to macrophages, slowly degrade their engulfed cargo and can provide fine control of lysosomal degradation for limited processing of internalized antigens2. Moreover, by virtue of pathogen-sensing molecules such as Toll-like receptors, DCs can decipher the antigen context, such as its association with bacterial lipopolysaccharide, and efficiently prime naive T cells, a prerequisite for memory formation. The central role of this host-defense mechanism that bridges innate and adaptive immunity was recognized by the awarding of the 2011 Nobel prize in physiology or medicine to its discoverers: Ralph Steinman, the so-untimely deceased father of the DC field, and Jules Hoffmann and Bruce Beutler, who identified the defensive role of Toll in insects and mammalian Toll-like receptor, respectively. In this issue of Nature Immunology, Busch and colleagues identify an intriguing mechanism by which evolution has dealt with the host's dilemma of balancing the need for maintenance of blood sterility and bacterial clearance with the ability to mount persistent protective immunity3. However, sophistication comes at a price: by redirecting bacteria from macrophages to DCs, the host reveals an Achilles' heel that can be exploited by pathogens as a staging point for dissemination (Fig. 1).

Figure 1: As part of the innate immune response, macrophages can engulf and destroy opsonized bacteria.

Marina Corral

Although this results in the clearance of bacteria, it can deprive the host of a source of antigens sufficient for the generation of an adaptive immune response (left). By virtue of the glycoprotein receptor GPIb, platelets bind deposits of C3 complement on the surface of blood-borne bacteria (right). The resulting platelet coat redirects complement-opsonized intruders from their rapid destruction by macrophages to a defined splenic DC subset, which allows priming of T cells and the establishment of immunological memory. However, these CD8α+ DCs can also serve as a beachhead for infection by facultative intracellular bacteria such as L. monocytogenes.

Almost a decade ago, an in vivo DC-ablation model demonstrated that DCs are critical for mounting cytotoxic T lymphocyte (CTL) responses to the bacterium Listeria monocytogenes4. Surprisingly, however, a subsequent study by the Busch group has shown that rather than being needed for antigen presentation and T cell priming, DCs are required by the facultative intracellular bacteria to seed the spleen and spread thereafter to the surrounding tissue5. This activity seems to be associated with a specific classical DC subset marked by CD8α expression, and indeed the role of CD8α+ DCs as an obligatory entry point for productive L. monocytogenes infection has been confirmed through the use of mice that specifically lack these cells due to deficiency in the BATF3 transcription factor6.

With the present study, Busch and colleagues revisit their earlier finding to investigate the requirements for the spleen colonization by L. monocytogenes, focusing on the complement system, previously linked to the spreading of bacteria in tissues. Indeed, mice deficient in the C3 complement component, an abundant serum molecule important for the opsonization of bacteria, have considerably fewer bacteria in their spleens after intravenous challenge with L. monocytogenes. Moreover, taking advantage of a strategy for transient depletion of C3 through the use of cobra venom, the authors establish that the C3 deficiency must coincide with the bacterial challenge but is ineffective when delayed for even an hour. Final direct evidence for the crucial role of opsonic C3 in colonization of the spleen is provided by experiments in which bacteria preincubated with wild-type serum (which supports C3 opsonization) or C3-deficient serum are then inoculated into C3-deficient mice. Strikingly, bacteria decorated with C3 fragment are better at seeding the spleen than are uncoated bacteria. Moreover, only bacteria decorated with C3 fragment are ingested by splenic CD8α+ DCs, which proves that opsonization channels bacteria toward the critical early entry route of bacterial colonization.

The next intriguing question is what directs the opsonized bacteria to the DC subset rather than to macrophages. Interestingly, within minutes of injection into wild-type mice, bacteria retrieved from the circulation are associated with platelets, as indicated by their staining with the membrane glycoprotein CD41. In contrast, bacteria do not cluster with platelets in C3-deficient mice, although platelet association in these mice is restored by preincubation of the bacteria with wild-type serum. Platelet association seems to be directly related to the splenic colonization, as depletion of platelets impairs the in vivo targeting of splenic CD8α+ DCs.

To identify the platelet surface receptor that binds the opsonized bacteria, the authors use an in vitro inhibition assay with a battery of monoclonal antibodies to platelet antigens. Interestingly, blockade of the glycoprotein GPIb (CD42b) specifically abrogates in vitro L. monocytogenes–platelet interactions. This proves to be physiologically relevant, as L. monocytogenes fail to enter splenic CD8α+ DCs in mice deficient in GPIb.

Having established that complement-mediated adherence to platelets targets L. monocytogenes to the critical early splenic CD8α+ DC survival niche, Busch and colleagues next assess its role in the ensuing antibacterial T cell immunity. Notably, CD8α+ DCs are equipped with a unique phagosome-to-cytosol (cross-presentation) pathway that allows them to present ingested exogenous antigens after processing in the context of major histocompatibility complex class I7. However, to achieve protective immunity to L. monocytogenes (that is, to detect and efficiently neutralize infected non-hematopoietic cells), CTLs must be primed against bacterial products secreted into the cytoplasm8. Through the use of a spread-deficient strain of L. monocytogenes (ΔActA), the authors show that C3-deficient mice and mice depleted of platelets mount significantly impaired CTL responses. This supports the notion that the platelet-mediated shuttling system is critical to the development of optimal T cell immunity to blood-borne L. monocytogenes, at least in part because the platelet association seems to protect the bacteria from immediate degradation by macrophages.

In the experiments described above, Busch and colleagues use L. monocytogenes, which although it is not a mouse pathogen is the favorite 'pet' of immunologists studying infection and has been instrumental in the identification of many fundamental aspects of pathogen handling9. Notably, the paper provides evidence that the C3-promoted association with platelets could be a broadly used host defense mechanism not restricted to just this bacterium. Thus, except for Streptococcus pneumonia, whose polysaccharide capsule prevents complement deposition, association with platelets is observed with all other Gram-positive bacterial strains tested, including Staphylococcus aureus, Enterococcus fecalis and Bacillus subtilis. This highlights the potential general importance of complement-mediated adherence to platelets in the establishment of antibacterial immunity, although this point and potential implications for the clinic clearly merit further study. However, the particular use of L. monocytogenes, a facultative intracellular pathogen, gives the present study an interesting additional twist; as shown before, these bacteria viciously exploit the DC-targeting route to escape their destruction in macrophages5,6. Moreover, this allows them to reach their unique survival niche of splenic CD8α+ DCs, which, while stimulating T cells, allow the bacteria to spread to neighboring cells through the use of their ingenious actin-based propelling mechanism and thereby disseminate in the infected tissues. This sequence of events highlights once more how the adaptive immune system with its sophistication selects for even more-devious pathogens, thus becoming the cause of its own necessity10.

The study of Busch and colleagues has many interesting facets related to the challenge of coordinating innate and adaptive host defense mechanism and the host-pathogen interplay. Most of these aspects have been touched on above. In conclusion, however, it is important to emphasize how this study provides a rare yet clear glimpse at the physiological 'division of labor' by the two main mononuclear phagocyte participants: the macrophage and the DC. The distinction between these cell types, historically based on anatomic location and surface markers, can often—especially to the outsider—seem arbitrary, although much progress has been made in defining the unique origins, genetic dependence and cell biology in this myeloid compartment11. Arguably, the best way to establish the existence of distinct cell populations with physiological relevance remains the assignment of specific functions—an approach that was pioneered for mononuclear phagocytes through the use of the cell-ablation strategy described above4 and was then complemented by the emergence of mouse mutants that lack defined DC subsets12. The study of Busch and colleagues is yet another showcase par excellence for the critical complementary roles of macrophages and DCs. Although the former evolutionarily older cells ensure host survival through the clearance of blood-borne bacteria, DCs, which are considered to have evolved with lymphocytes, bridge innate and adaptive immunity and thus enable the host to establish long-lasting protective immunity.


  1. 1

    Delamarre, L., Pack, M., Chang, H., Mellman, I. & Trombetta, E.S. Science 307, 1630–1634 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Savina, A. et al. Cell 126, 205–218 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Verschoor, A. et al. Nat. Immunol. 12, 1194–1201 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Jung, S. et al. Immunity 17, 211–220 (2002).

    CAS  Article  Google Scholar 

  5. 5

    Neuenhahn, M. et al. Immunity 25, 619–630 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Edelson, B.T. et al. Immunity 35, 236–248 (2011).

    CAS  Article  Google Scholar 

  7. 7

    Bevan, M.J. J. Exp. Med. 143, 1283–1288 (1976).

    CAS  Article  Google Scholar 

  8. 8

    Shen, H. et al. Cell 92, 535–545 (1998).

    CAS  Article  Google Scholar 

  9. 9

    Pamer, E.G. Nat. Rev. Immunol. 4, 812–823 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Hedrick, S.M. Immunity 21, 607–615 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Geissmann, F. et al. Science 327, 656–661 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Hashimoto, D., Miller, J. & Merad, M. Immunity 35, 323–335 (2011).

    CAS  Article  Google Scholar 

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Correspondence to Steffen Jung.

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Jung, S. A rescue gone wrong. Nat Immunol 12, 1137–1138 (2011). https://doi.org/10.1038/ni.2161

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