Efficient and versatile manipulation of the peripheral CD4+ T‐cell compartment by antigen targeting to DNGR‐1/CLEC9A

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Abstract
DC NK lectin group receptor‐1 (DNGR‐1, also known as CLEC9A) is a C‐type lectin receptor expressed by mouse CD8α+ DC and by their putative equivalents in human. DNGR‐1 senses necrosis and regulates CD8+ T‐cell cross‐priming to dead‐cell‐associated antigens. In addition, DNGR‐1 is a target for selective in vivo delivery of antigens to DC and the induction of CD8+ T‐cell and Ab responses. In this study, we evaluated whether DNGR‐1 targeting can be additionally used to manipulate antigen‐specific CD4+ T lymphocytes. Injection of small amounts of antigen‐coupled anti‐DNGR‐1 mAb into mice promoted MHC class II antigen presentation selectively by CD8α+ DC. In the steady state, this was sufficient to induce proliferation of antigen‐specific naïve CD4+ T cells and to drive their differentiation into Foxp3+ regulatory lymphocytes. Co‐administration of adjuvants prevented this induction of tolerance and promoted immunity. Notably, distinct adjuvants allowed qualitative modulation of CD4+ T‐cell behavior: poly I:C induced a strong IL‐12‐independent Th1 response, whereas curdlan led to the priming of Th17 cells. Thus, antigen targeting to DNGR‐1 is a versatile approach for inducing functionally distinct CD4+ T‐cell responses. Given the restricted pattern of expression of DNGR‐1 across species, this strategy could prove useful for developing immunotherapy protocols in humans.