Biology subjects

Sutton, M. S.

Publications and source records attributed to Sutton, M. S..

4 recordsLinked to original sources

bioRxiv2024

CD4 T cells and CD8α+ lymphocytes are necessary for intravenous BCG-induced protection against tuberculosis in macaques

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose of BCG vaccination from 5{xi}105 CFU ID to 5{xi}107 CFU intravenous (IV) resulted in prevention of infection and disease in a rigorous, highly susceptible non-human primate model of TB. Identifying the immune mechanisms of protection for IV BCG will facilitate development of more effective vaccines against TB. Here, we depleted select lymphocyte subsets in IV BCG vaccinated macaques prior to Mtb challenge to determine the cell types necessary for that protection. Depletion of CD4 T cells or all CD8 expressing lymphoycytes (both innate and adaptive) resulted in loss of protection in most macaques, concomitant with increased bacterial burdens ([~]4-5 log10 thoracic CFU) and dissemination of infection. In contrast, depletion of only adaptive CD8{beta}+ T cells did not significantly reduce protection against disease. Our results demonstrate that CD4 T cells and innate CD8+ lymphocytes are critical for IV BCG-induced protection, supporting investigation of how eliciting these cells and their functions can improve future TB vaccines. One Sentence SummaryAntibody depletion of lymphocytes in rhesus macques demonstrates key roles for CD4 T cells and innate-like CD8+ lymphocytes in conferring sterilizing immunity against tuberculosis following intravenous BCG vaccination.

immunology↗

bioRxiv2023

Antibody-mediated depletion of select T cell subsets in blood and tissue of nonhuman primates

Understanding the immunological control of pathogens requires a detailed evaluation of the mechanistic contributions of individual cell types within the immune system. While knockout mouse models that lack certain cell types have been used to help define the role of those cells, the biological and physiological characteristics of mice do not necessarily recapitulate that of a human. To overcome some of these differences, studies often look towards nonhuman primates (NHPs) due to their close phylogenetic relationship to humans. To evaluate the immunological role of select cell types, the NHP model provides distinct advantages since NHP more closely mirror the disease manifestations and immunological characteristics of humans. However, many of the experimental manipulations routinely used in mice (e.g., gene knock-out) cannot be used with the NHP model. As an alternative, the in vivo infusion of monoclonal antibodies that target surface proteins on specific cells to either functionally inhibit or deplete cells can be a useful tool. Such depleting antibodies have been used in NHP studies to address immunological mechanisms of action. In these studies, the extent of depletion has generally been reported for blood, but not thoroughly assessed in tissues. Here, we evaluated four depleting regimens that primarily target T cells in NHP: anti-CD4, anti-CD8, anti-CD8{beta}, and immunotoxin-conjugated anti-CD3. We evaluated these treatments in healthy unvaccinated and IV BCG-vaccinated NHP to measure the extent that vaccine-elicited T cells - which may be activated, increased in number, or resident in specific tissues - are depleted compared to resting populations in unvaccinated NHPs. We report quantitative measurements of in vivo depletion at multiple tissue sites providing insight into the range of cell types depleted by a given mAb. While we found substantial depletion of target cell types in blood and tissue of many animals, residual cells remained, often residing within tissue. Notably, we find that animal-to-animal variation is substantial and consequently studies that use these reagents should be powered accordingly.

immunology↗

bioRxiv2019

Extensive CD8β depletion does not prevent control of viral replication or protection from challenge in macaques chronically infected with a live attenuated simian immunodeficiency virus

We evaluated the contribution of CD8{beta}+ T cells on control of live-attenuated simian immunodeficiency virus (LASIV) replication during chronic infection and subsequent protection from pathogenic SIV challenge. Unlike previous reports with a CD8-specific depleting monoclonal antibody (mAb), the CD8{beta}-specific mAb CD8{beta}255R1 selectively depleted CD8{beta}+ T cells without also depleting non-CD8+ T cell populations that express CD8, such as natural killer (NK) cells and {gamma}{delta} T cells. Following infusion with CD8{beta}255R1, plasma viremia transiently increased coincident with declining peripheral CD8{beta}+ T cells. Interestingly, plasma viremia returned to pre-depletion levels even when peripheral CD8{beta}+ T cells did not. Although depletion of CD8{beta}+ T cells in the lymph node (LN) was incomplete, frequencies of these cells were three-fold lower (p=0.006) in animals that received CD8{beta}255R1 compared to control IgG. It is possible that these residual SIV-specific CD8{beta}+ T cells may have contributed to suppression of viremia during chronic infection. We also determined whether infusion of CD8{beta}255R1 in the LASIV-vaccinated animals increased their susceptibility to infection following intravenous challenge with pathogenic SIVmac239. We found that 7/8 animals infused with CD8{beta}255R1, and 3/4 animals infused with the control IgG, were resistant to SIVmac239 infection. These results suggest that infusion with CD8{beta}255R1 did not eliminate the protection afforded to LASIV vaccination. This provides a comprehensive description of the impact of CD8{beta}255R1 infusion on the immunological composition of the host, when compared to an isotype matched control IgG, while showing that the control of LASIV viremia and protection from challenge can occur even after CD8{beta}255R1 administration.\n\nImportanceStudies of SIV-infected macaques that deplete CD8+ T cells in vivo with monoclonal antibodies have provided compelling evidence for their direct antiviral role. These studies utilized CD8-specific mAbs that target both the major (CD8{beta}+) and minor (CD8+) populations of CD8+ T cells, but additionally deplete non-CD8+ T cell populations that express CD8, such as NK cells and {gamma}{delta} T cells. In the current study, we administered the CD8{beta}-specific depleting mAb CD8{beta}255R1 to cynomolgus macaques chronically infected with a LASIV to selectively deplete CD8{beta}+ T cells without removing CD8+ lymphocytes. We evaluated the impact on control of virus replication and protection from pathogenic SIVmac239 challenge. These results underscore the utility of CD8{beta}255R1 for studying the direct contribution of CD8{beta}+ T cells in various disease states.

immunology↗

bioRxiv2018

Acute-phase CD4+ T cell responses targeting invariant viral regions are associated with control of live-attenuated simian immunodeficiency virus

We manipulated SIVmac239{Delta}nef, a model of MHC-independent viral control, to evaluate characteristics of effective cellular responses mounted by Mauritian cynomolgus macaques (MCMs) who express the M3 MHC haplotype that has been associated with poor control of pathogenic SIV. We created SIV{Delta}nef-8x to test the hypothesis that effective SIV-specific T cell responses targeting invariant viral regions can emerge in the absence of immunodominant CD8+ T cell responses targeting variable epitopes, and that control is achievable in individuals lacking known protective MHC alleles. Full proteome IFN{gamma} ELISPOT assays identified six newly targeted immunogenic regions following SIV{Delta}nef-8x infection of M3/M3 MCMs. We deep sequenced circulating virus and found that four of the six newly targeted regions rarely accumulated mutations. Six animals infected with SIV{Delta}nef-8x targeted at least one of the four invariant regions and had a lower set point viral load compared to two animals that did not target any invariant regions. We found that MHC class II molecules restricted all four of the invariant peptide regions, while the two variable regions were restricted by MHC class I molecules. Therefore, in the absence of immunodominant CD8+ T cell responses that target variable regions during SIVmac239{Delta}nef infection, individuals without protective MHC alleles developed predominantly CD4+ T cell responses specific for invariant regions that may improve control of virus replication. Our results provide some evidence that antiviral CD4+ T cells during acute SIV infection can contribute to effective viral control and should be considered in strategies to combat HIV infection.\n\nImportanceStudies defining effective cellular immune responses to human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have largely focused on a rare population that express specific MHC class I alleles and control virus replication in the absence of antiretroviral treatment. This leaves in question whether similar effective immune responses can be achieved in the larger population. The majority of HIV-infected individuals mount CD8+ T cell responses that target variable viral regions that accumulate high-frequency escape mutations. Limiting T cell responses to these variable regions and targeting invariant viral regions, similar to observations in rare elite controllers, may provide an ideal strategy for the development of effective T cell responses in individuals with diverse MHC genetics. Therefore, it is paramount to determine whether T cell responses can be redirected towards invariant viral regions in individuals without protective MHC alleles and if these responses improve control of virus replication.

immunology↗