Whether nonclassical monocytes interact with and influence atherogenic T cell responses remains unclear; however, recent evidence indicates that patrolling monocytes are able to present antigens within the vasculature to effector CD4+ T cells [96]. The persistence of undifferentiated monocytes within the plaque has yet to be determined, in part because the aforementioned studies have not included markers for distinguishing monocytes from macrophages and DCs. monocytesDisplay increased CCL3, CCL4, and CCL5 within lung tumor metastases [7].Lymphocyte RecruitmentAtherosclerotic plaquesMonocyteFunctionT cell interactionClassical monocytesDifferentiate into CD11bhiCD11hi cells expressing CD80 and CD86;[34]. Whether this subset is related to the previously-identified mice bearing B16 tumors, a populace of Ly6C+CD103+ monocyte-derived cells cross-present antigens and re-activate anergic CD8+ T cells [70] (Physique 1, Table 1). Maturation into macrophages/DCs is likely 7CKA required for cross-presentation, as monocytes derived from human lung tumors are unable to present tumor antigens, while macrophages from your same tumors can cross-present and stimulate IFN? production by antigen-specific effector T cells [71]. Interestingly, tumor antigen in 7CKA metastatic lung sites is usually redirected from macrophages to cDCs in CCR2-deficient mice, indicating that different APCs may compete for tumor antigen [44]. Additionally, monocytes may most effectively contribute to anti-tumoral immunity, especially in Occasions with sufficient numbers of cDCs, by transporting antigen to lymphoid organs before transfer to APCs [72]. Costimulatory and Coinhibitory Molecules Myeloid cells impact the strength of T cell receptor signaling and downstream T cell responses by surface expression of costimulatory and coinhibitory molecules [73]. In peripheral blood, the costimulatory molecule CD86 is usually universally expressed across monocyte subsets, while CD80 is usually lowly expressed at homeostasis [29]. In mice, expression of the coinhibitory molecule programmed death ligand 1 (PD-L1) is restricted to nonclassical Ly6Clo monocytes 7CKA at homeostasis [74], but appears to be broadly induced in both classical Ly6Chi monocytes and myeloid progenitors in mice bearing B16 melanoma tumors [75]. Monocytes upregulate both the PD-L1/2 and CD80/CD86 pathways as they enter the TIME and differentiate into TAMs [76]. Tumor-derived RNA may serve as one of the signals regulating expression of coinhibitory molecules in monocytes, as RNA-loaded exosomes derived from Mouse monoclonal to p53 7CKA leukemic cells increase PD-L1 expression in human monocytes [77]. Interestingly, the receptor for PD-L1/2, programmed cell death protein-1 (PD-1), is also absent from monocytes during homeostasis, but induced in tumor-bearing mice [75] CD28 expressed on naive T cells binds to CD80 and CD86 expressed on APCs, and interactions between CD28 with CD80/CD86 are critical for facilitating memory and effector T cell formation [78]. Costimulation by CD86 generally promotes T cell activation, but CD86 can also inhibit this process through conversation with CTLA-4. In monocyte-derived TAM precursors recruited to lung metastases, CD86 suppresses CD8+ T cell-mediated tumor cell cytotoxicity through CTLA-4 [76]. Consequently, anti-CTLA-4 immunotherapy (currently approved for treatment of metastatic melanoma and renal cell carcinoma [79]) may take action in part by interfering with interactions between immunosuppressive monocyte-derived cells and T cells, although this requires further investigation. Recent work exhibited that increased PD-1 expression on myeloid cells in tumor-bearing mice prospects to enhanced production of myeloid progenitors and 7CKA MDSCs that suppress T cell responses [75]. Immune checkpoint inhibitors targeting PD-1 and PD-L1/2 have been highly successful in subsets of non-small cell lung malignancy, renal cell carcinoma, melanoma, and other solid tumor patients [79], but whether these therapies inhibit monocyte-T cell interactions remains unclear. Melanoma patients with higher baseline levels of classical monocytes display superior clinical responses and survival following anti-PD-1 treatment [52], providing evidence that monocyte-T cell interactions may contribute to therapies targeting PD-1:PD-L1/2 signaling. Additionally, monocytes can express OX40L, CD137L, and CD40 [80C82], which are currently under investigation as drug targets for malignancy immunotherapy. Multiple Phase I and Phase II clinical trials are underway to examine the security and efficacy of CD40 monoclonal antibodies in solid tumors [83]. Whether these molecules regulate crosstalk between monocytes and T cells in malignancy, and the extent to which these interactions may be targeted clinically to increase anti-tumoral immunity will be of interest as further research is performed in this area. Monocyte-T Cell Interactions in Atherosclerosis Classical Ly6Chi monocytes (Table 1, Physique 2) represent the first immune cell populace to arrive at the atherosclerotic plaque via recruitment by CCR2-CCL2, CX3CR1-CX3CL1, and CCR5-CCL5 signaling [84,85]. Ly6Chi monocyte frequencies double every month in atherosclerotic Apolipoprotein E-deficient (ApoE?/?) mice fed a Western (high-cholesterol) diet [84]. Once recruited to the vessel wall, Ly6Chi monocytes differentiate into CD11bhiCD11chi cells and upregulate the costimulatory molecules CD80 and CD86 [86C89], suggesting acquisition of APC capacity [90]. Many of these cells also express F4/80, indicating that plaque monocytes may differentiate into both DCs and macrophages. Open in a separate.