Pulmonary CD103+ dendritic cells: key regulators of immunity against infection

Since the discovery of dendritic cells (DCs) by the Nobel laureate Professor Ralph Steinman et al. in 1973, a plethora of literature has accumulated on the functional roles of DCs in humans and animal models.¹ DCs are involved in the innate sensing and modulation of adaptive immunity to pathogens. CD103+ DCs constitute a classical nonlymphoid DC subset that has an important role in generating immunity and maintaining tolerance.² Pulmonary CD103+ DCs (CD103+ PDCs), which reside in close association with the airway epithelium, are particularly critical in controlling T-cell immunity against lung infections.^2,3 In this article, we discuss recent evidence that shines light on the role and mechanism of CD103+ PDCs in modulating CD8+ and CD4+ T-cell responses against various pathogens, including bacteria and viruses. A deeper understanding of CD103+ PDC function may provide new translational avenues for the development of vaccines and therapeutics against infectious diseases.

Mouse CD103+ PDCs are phenotypically characterized by the expression of α_E(CD103)β₇, CD11c^hi, CD207, MHC-II, TLR3, XCR1, and Clec9a/DNGR1 but not CD64 and CD11b.³ The transcription factors Batf3 and Irf8 are critical for the development of CD103+ PDCs, as shown by the lack of these DCs in Batf3- or Irf8-deficient mice.³ Following pulmonary infection, CD103+ PDCs upregulate costimulatory molecules (CD40, CD80, and CD86), produce large quantities of several cytokines (IL-4, IL-13, IL-12, IL-10, IL-23, and IL-6), migrate to the lung-draining mediastinal lymph nodes, and prime naive CD4+ and CD8+ T cells to induce antigen-specific immune responses.^4–6 Recent studies indicate that CD103+ DCs, along with lymphoid CD8α+ DCs, form a new class of DCs referred to as type 1 DCs (DC1s), which express the chemokine receptor XCR1 and perform the unique function of cross-presenting exogenous antigens with MHC-I molecules to CD8+ T cells.⁷ Owing to similar phenotypic and functional characteristics, human CD141/BDCA-3+ DCs are considered equivalent to murine DC1s.⁸ Overall, these DCs constitute a unified DC subset in mice and humans that is developmentally and functionally related.

An accumulating wealth of evidence stemming from mouse studies has focused on the function of CD103+ PDCs during viral and bacterial infections.^4,6,9 Upon challenge with respiratory influenza A virus or poxvirus infection, mice that lack CD103+ DCs, such as Batf3^−/− and Clec9A− diphtheria toxin receptor transgenic mice, failed to induce protective immunity, in contrast to control mice, suggesting a protective role for CD103+ PDCs in viral infections.^6,9,10 Following influenza A virus infection, CD103+ PDCs acquired and processed apoptotic cell-associated viral antigens in their endocytic compartment, migrated to the mediastinal lymph nodes, and cross-presented the antigens on MHC-I molecules to naive CD8+ T cells to elicit protective virus-specific cytotoxic responses.^6,11 Interestingly, CD103+ PDCs could cross-present antigens from virally infected cells because of their ability to resist infection by influenza virus via a type I interferon-mediated antiviral state.⁶ On the other hand, ablation of CD103+ PDCs resulted in decreased production of IFN-γ by CD8+ T cells and reduced expression of the activation and transcription markers Ki67, CD25, and T-bet in these cells after respiratory vaccinia virus infection.¹⁰ Liang Ng et al.¹² have further shown that CD103+ PDCs not only control cross-priming of CD8+ T cells but also regulate their migration, viability, and memory responses during influenza infection. In doing so, CD103+ PDCs induce upregulated levels of sphingosine-1-phosphate receptor, which is important for egress of lymphocytes from the lymph nodes, on activated CD8+ T cells¹². Moreover, adoptive transfer of bone marrow-derived CD103+ DCs in CD103+ DC-ablated mice promoted the survival of virus-specific effector CD8+ T cells.¹² In addition, CD103+ PDCs purified from the lungs of influenza virus-infected mice expressed an enhanced level of IL-15, which is a critical cytokine for the maintenance of naive and memory T cells.¹² Thus, CD103+ PDCs occupy a central position in regulating various aspects of CD8+ T-cell responses against viral infections.

Hemann et al.¹³ recently elucidated the immune mechanism that directs CD103+ PDCs to modulate antiviral CD8+ T-cell immunity. Mice lacking the receptor (Ifnlr1^−/−) of type III interferon (IFN-λ), which is an immune-modulatory cytokine that has the ability to promote CD8+ T-cell immunity against influenza A virus, showed a significant reduction in migratory CD103+ PDCs, along with CD8α+ DCs, in the mediastinal lymph nodes after influenza A virus infection.¹³ Furthermore, specific deletion of IFN-λ receptor 1 in CD11c+ DCs in a conditional knockout mouse model mirrored the global immune phenotype of Ifnlr1^−/− mice, particularly the diminished CD8+ T-cell responses.¹³ Taken together, these findings indicate that IFN-λ signaling has an important role in programming CD103+ PDCs for migration from the lungs to the lymph nodes and induction of an optimal CD8+ T-cell response against influenza A virus. Provided the importance of the CD103+ PDC-IFN-λ-CD8+ T-cell axis in adaptive immunity, it may be prudent to exploit IFN-λ as a vaccine adjuvant against influenza infection.

Most information on how CD103+ PDCs control CD4+ T-cell responses comes from studies using bacterial and fungal pathogens.^4,5,14,15 Analysis of CD103+ PDCs from Klebsiella pneumoniae-infected mice showed that the PDCs imparted enhanced antigen-specific CD4+ T-cell responses in an in vitro DC-T-cell coculture system with OVA TCR transgenic CD4+ T helper cells.⁵ Recently, we assessed the immune function of classical major PDC subsets, CD103+ and CD11b^hi PDCs, in a mouse model of pulmonary chlamydial infection.⁴ Intranasal transfer of CD103+ PDCs isolated from Chlamydia muridarum-infected mice into naive mice induced better protection against C. muridarum challenge infection than that in CD11b^hi PDC recipients.⁴ Analysis of cytokines in CD103+ PDC recipients clearly showed a stronger bias toward Th1 (IFN- γ) and Th17 (IL-17) responses than that in mice receiving CD11b^hi PDCs. These data suggest a predominant role for the CD103+ PDC subset over CD11b^hi PDCs in conferring protective Th1/Th17 immunity to chlamydial infection. In accordance with these findings, depletion of CD103+ PDCs in mice resulted in increased bacterial burdens in the lungs and lymph nodes following Mycobacterium tuberculosis infection, which was associated with consistently reduced levels of total and activated CD4+ and CD8+ T cells and Th1-related cytokines (IFN-γ and TNF-α).¹⁴ Using a mouse model of pulmonary Aspergillus fumigatus infection, Zelante et al.¹⁵ deciphered the mechanisms by which CD103+ PDCs control CD4+ cell function in the lungs. A. fumigatus triggers CD103+ PDCs to secrete IL-2 through the receptor dectin-1, phagocytosis, and Ca²⁺-calmodulin-dependent NFAT signaling pathway, thus eliciting IL-17+ CD4+ T-cell responses that induce protective immunity.¹⁵ On the other hand, CD103+ PDCs incompetent for IL-2 production produce IL-23, which in turn causes lethal Th17-driven hyperinflammation.¹⁵ In summary, the equilibrium between CD103+ PDC-expressed IL-2 and IL-23 is critical for modulating mucosal pulmonary responses to infection.

CD103+ PDCs are critical to adaptive immunity against pulmonary infections. They not only excel in cross-priming CD8+ T cells to generate antigen-specific cytotoxic responses against viruses but also induce effective CD4+ T-cell immunity (Th1/Th17) to bacterial and fungal pathogens (Fig. 1). Indeed, a multifaceted role for CD103+ PDCs in pathogen defense is becoming clearer in light of new knowledge originating from various mouse studies. The indispensability of CD103+ PDCs for the generation and maintenance of protective antiviral T cells suggests that vaccination strategies should target these DCs to achieve optimal immunity. Modulation of CD103+ PDC function may have implications for both ensuing protective immunity and suppressing infection-driven hyperinflammation in the lungs. The relevance of data accumulated regarding murine CD103+ PDCs for humans warrants further exploration. The similarity of human CD141+ DCs to murine CD103+ DCs presents an opportunity to establish a functional correlation between these two DC subsets in mice and humans during infection. Moving in this direction, humanized mice have emerged as an attractive model to study CD141+ DC function in vivo under naive and infectious conditions. This advance is owing mainly to the striking functional similarities of CD141+ DCs from humanized mice, such as cross-priming and IFN-λ expression, with those found in the human blood.¹⁶

Fig. 1.

CD103+ PDC-mediated T-cell responses to pathogens. Following a respiratory infection with pathogens, CD103+ PDCs acquire and process microbial antigens, express costimulatory molecules (e.g., CD80, CD86, and CD40), secrete multiple cytokines (e.g., IL-23, IL-12, and IL-10), and migrate to the lung-draining lymph nodes to present the antigens on MHC-I/MHC-II molecules to the TCR of naive CD8+/CD4+ T cells, inducing cytotoxic/T helper (Th1/17) responses against viral and bacterial pathogens. PDC pulmonary dendritic cell, IL Interleukin, MHC major histocompatibility complex, TCR T-cell receptor, B bacterium, V virus

Author contributions

SS and XY wrote the manuscript and gave approval of its last version to be published.

Competing interests

The authors declare no competing interests.