Suppression of Immunodominant Antitumor and Antiviral CD8+ T Cell Responses by Indoleamine 2,3-Dioxygenase

Abstract

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme known to suppress antitumor CD8+ T cells (TCD8). The role of IDO in regulation of antiviral TCD8 responses is far less clear. In addition, whether IDO controls both immunodominant and subdominant TCD8 is not fully understood. This is an important question because the dominance status of tumor- and virus-specific TCD8 may determine their significance in protective immunity and in vaccine design. We evaluated the magnitude and breadth of cross-primed TCD8 responses to simian virus 40 (SV40) large T antigen as well as primary and recall TCD8 responses to influenza A virus (IAV) in the absence or presence of IDO. IDO−/− mice and wild-type mice treated with 1-methyl-D-tryptophan, a pharmacological inhibitor of IDO, exhibited augmented responses to immunodominant epitopes encoded by T antigen and IAV. IDO-mediated suppression of these responses was independent of CD4+CD25+FoxP3+ regulatory T cells, which remained numerically and functionally intact in IDO−/− mice. Treatment with L-kynurenine failed to inhibit TCD8 responses, indicating that tryptophan metabolites are not responsible for the suppressive effect of IDO in our models. Immunodominant T antigen-specific TCD8 from IDO−/− mice showed increased Ki-67 expression, suggesting that they may have acquired a more vigorous proliferative capacity in vivo. In conclusion, IDO suppresses immunodominant TCD8 responses to tumor and viral antigens. Our work also demonstrates that systemic primary and recall TCD8 responses to IAV are controlled by IDO. Inhibition of IDO thus represents an attractive adjuvant strategy in boosting anticancer and antiviral TCD8 targeting highly immunogenic antigens.

PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination

“…The allospecific response in this model can be detected after brief ex vivo stimulation of splenocytes with either H-2 d+ T Ag + cells ( e.g ., KD2SV) or H-2 d+ T Ag − cells ( e.g ., P815) (39, 40). In the experiment depicted in Fig.…”

“…For example, when we inhibited IDO (39) or used an immunostimulatory dose of the mTOR inhibitor rapamycin (40), we could only boost the dominant response to site IV. Therefore, it appears that SDD-specific T CD8 responses are refractory to many forms of treatment.…”

“…3A–C). Another tempting possibility that merits consideration is to combine PD-1-targeted therapies with approaches or agents that strengthen IDD-specific T CD8 , such as IDO and mTOR inhibitors (39, 40) among many others, in appropriate settings, in order to boost SDD- and IDD-specific clones alike.…”

“…Bone marrow-derived DCs (BMDCs) were generated by culturing marrow cells with recombinant mouse GM-CSF and IL-4 as previously described (39), and matured using 100 ng/mL LPS during the final 16 h of the culture. Adherent and floating DCs were harvested and pulsed for 2 h at 37°C with synthetic peptides corresponding to T Ag’s site I and/or site IV (Table 1) at a final concentration of 1 µM.…”

“…This intriguing phenomenon is called immunodominance (ID) (25). We and others have demonstrated that T CD8 ID can be shaped by Ag dose and administration route (26, 27), T CD8 priming pathway ( i.e ., direct priming versus cross-priming) (28) and the type of APCs involved (29), abundance of protein substrates (30), efficiency and kinetics of peptide liberation by standard proteasomes and immunoproteasomes (31, 32), degenerate selectivity of TAP for peptides (33), peptide binding affinity for MHC class I allomorphs (33, 34), presence and precursor frequency of cognate T CD8 in one’s T cell repertoire (35), TCR structural diversity, for instance due to N-nucleotide addition within junctional sequences (36, 37), selective suppression of T CD8 responses by naturally occurring regulatory T (nTreg) cells (38), and immunomodulatory actions of certain intracellular enzymes such as IDO (39) and mammalian target of rapamycin (mTOR) (40). Additionally, immunodominant T CD8 clones may outcompete subdominant clones for access to APCs (41) or even directly kill them although the evidence for the latter scenario has been scarce.…”