Vaccine-assisting molecules help the lung memorize immune responses

Traditional vaccines are generally better at eliciting antibody responses rather than building a memory of cellular immunity involving dedicated T cell subsets. Vaccines directed towards infections such as HIV or cancers would be vastly improved if they could elicit these responses more efficiently. New research uncovers a mechanism to establish such a memory in the lung which is conserved in mice, non-human primates and humans.

Isabel Hofman

The mammalian immune response consists of two essential pillars employing complementary tactics to combat infections. One is based on antibody production by activated B cells, while the other strategy relies on direct cell-to-cell contact by activated T cells. Both of these responses are induced within days of the infection while also generating a set of memory cells that will be present long afterwards and can be reactivated upon a second encounter with the pathogen. Vaccines rely on the induction of this immune memory for their protective effects but usually induce mostly antibody responses and little cellular immunity. This approach is effective against extracellular infections but much less useful against intracellular viruses such as HIV or malignant growth of the host cells. As these would be more effectively targeted by cytotoxic T cells, vaccines against these diseases need to efficiently induce this type of cellular immunity.

The group led by Karin Loré at KI, in collaboration with other groups including the Ross Kedl group at University of Colorado in Denver USA, has been investigating how to accomplish this. Previously published mice work showed that combined administration of two vaccine additives, termed adjuvants, can induce potent T-cell activation – over 10-fold higher than either adjuvant alone.1-3 Follow-up work in non-human primates showed that not only were the T cells stimulated to proliferate acutely, a population of tissue-resident memory T cells (TRM) was induced specifically in the lung of the treated animals.4 Their newest work uncovers the mechanism behind this memory formation.5

Using the same combination of adjuvants, poly I:C and anti-CD40 antibody, non-human primates were immunized against a HIV antigen via two routes of administration: intravenously (i.v.) and subcutaneously (s.c.). Both lead to robust T-cell responses but i.v. injected animals had larger populations of TRM cells in the lungs, identified by their CD103 expression. Intriguingly, the presence of this TRM population in the lungs three weeks post-immunization also strongly correlated with elevated IL10 levels six hours after injection.

An in vitro system using antigen-presenting cells (APC) purified from human blood or skin tissue was then used to investigate the underlying mechanisms of the in vivo phenotypes further. In this model, only the APCs from the blood produced IL10, with monocytes producing the largest amounts of the cytokine. APCs purified from blood were also the only ones able to increase CD103 expression on the cytotoxic T cells. Adding anti-IL10 antibody could block the positive effect of the APCs while adding IL10 together with APCs could stimulate expression of CD103 on the T cells without addition of the adjuvants. Adding IL10 alone without APCs did not have the same effect, suggesting that IL10 does not stimulate the T cells directly but rather primes the APCs into inducing TRM phenotypes. This role for IL10 in inducing CD103 expression is novel, however previous reports did link levels of transforming growth factor β (TGF-β) to higher levels of CD103 expression.6, 7 Indeed, the blood-derived monocytes expressed high levels of surface TGF-β, which was reduced upon IL10 stimulation and linearly correlated with how much TGF-β could be subsequently measured in the supernatant of the cultures.

Vaccination with the help of specific adjuvants induces monocytes to produce signalling molecules such as IL10 and TGF-β which in turn can support T cell memory in the lung.
Vaccination with the help of specific adjuvants induces monocytes to produce signalling molecules such as IL10 and TGF-β which in turn can support T cell memory in the lung.

In summary, the study shows that the adjuvants poly I:C and anti-CD40 induce monocytes to produce IL10 which in turn, in an autocrine fashion, primes them into releasing TGF-β. This factor then leads to memory phenotypes, specifically in resident T cells in the lung. I.v. delivery of these adjuvants could thus be a useful strategy for vaccinations against lung diseases such as pulmonary viruses or lung cancers. Moreover, given this newly uncovered role of IL10, it is promising that its use in humans has already proven capable of inducing antitumor activity.8, 9 As a proof of concept, this study might thus contribute to broader advances in the recruitment of cellular immunity after vaccination and in cancer immunotherapy.

References

1.            Ahonen, C.L., et al., Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFN. J Exp Med, 2004. 199(6): p. 775-784.

2.            Sanchez, P.J., et al., Combined TLR/CD40 Stimulation Mediates Potent Cellular Immunity by Regulating Dendritic Cell Expression of CD70 In Vivo. J Immunology, 2007. 178(3): p. 1564-1572.

3.            McWilliams, J.A., et al., Multiple innate signaling pathways cooperate with CD40 to induce potent, CD70-dependent cellular immunity. Vaccine, 2010. 28(6): p. 1468-76.

4.            Thompson, E.A., et al., Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates. J Immunology, 2015. 195(3): p. 1015-1024.

5.            Thompson, E.A., et al., Monocytes Acquire the Ability to Prime Tissue-Resident T Cells via IL-10-Mediated TGF-beta Release. Cell Rep, 2019. 28(5): p. 1127-1135 e4.

6.            Casey, K.A., et al., Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J Immunol, 2012. 188(10): p. 4866-75.

7.            Mackay, L.K., et al., T-box Transcription Factors Combine with the Cytokines TGF-beta and IL-15 to Control Tissue-Resident Memory T Cell Fate. Immunity, 2015. 43(6): p. 1101-11.

8.            Mumm, J.B., et al., IL-10 elicits IFNgamma-dependent tumor immune surveillance. Cancer Cell, 2011. 20(6): p. 781-96.

9.            Naing, A., et al., Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors. J Clin Oncol, 2016. 34(29): p. 3562-3569.

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