Dr. Hartigan-O'Connor is an Assistant Professor of Medicine at the University of California, Davis. His research is focused on mechanisms of tolerance and immune privilege, both in the adult eye and in the developing fetus. His most recent work focuses on resilience of retinal immune privilege to inflammatory insults and neovascularization, as well as the potential of immunosuppressive drugs to maintain privilege despite these challenges. His work has been published in leading journals including Science Translational Medicine and the Journal of Experimental Medicine.
Neutralization of rhesus cytomegalovirus IL-10 reduces horizontal transmission and alters long-term immunity.
Proc Natl Acad Sci U S A. 2019 Jun 12;:
Authors: Deere JD, Chang WLW, Villalobos A, Schmidt KA, Deshpande A, Castillo LD, Fike J, Walter MR, Barry PA, Hartigan-O'Connor DJ
Human cytomegalovirus (HCMV) causes severe disease in infants and immunocompromised people. There is no approved HCMV vaccine, and vaccine development strategies are complicated by evidence of both persistent infection and reinfection of people with prior immunity. The greatest emphasis has been placed on reducing transmission to seronegative pregnant women to prevent vertical transmission and its potentially severe sequelae. Increasing evidence suggests that the earliest host-HCMV interactions establish conditions for viral persistence, including evasion of host immune responses to the virus. Using a nonhuman primate model of HCMV infection, we show that rhesus macaques immunized against viral interleukin-10 (IL-10) manifest delayed rhesus cytomegalovirus (RhCMV) acquisition and altered immune responses to the infection when it does occur. Among animals with the greatest antiviral IL-10-neutralizing activity, the timing of RhCMV seroconversion was delayed by an average of 12 weeks. After acquisition, such animals displayed an antibody response to the new infection, which peaked as expected after 2 weeks but then declined rapidly. In contrast, surprisingly, vaccination with glycoprotein B (gB) protein had no discernible impact on these outcomes. Our results demonstrate that viral IL-10 is a key regulator of successful host immune responses to RhCMV. Viral IL-10 is, therefore, an important target for vaccine strategies against cytomegalovirus (CMV). Furthermore, given the immunoregulatory function of viral IL-10, targeting this protein may prove synergistic with other vaccine therapies and targets. Our study also provides additional evidence that the earliest host-CMV interactions can have a significant impact on the nature of persistent infection.
PMID: 31189602 [PubMed - as supplied by publisher]
Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.
Nat Med. 2018 Nov 12;:
Authors: Wang Z, Aguilar EG, Luna JI, Dunai C, Khuat LT, Le CT, Mirsoian A, Minnar CM, Stoffel KM, Sturgill IR, Grossenbacher SK, Withers SS, Rebhun RB, Hartigan-O'Connor DJ, Méndez-Lagares G, Tarantal AF, Isseroff RR, Griffith TS, Schalper KA, Merleev A, Saha A, Maverakis E, Kelly K, Aljumaily R, Ibrahimi S, Mukherjee S, Machiorlatti M, Vesely SK, Longo DL, Blazar BR, Canter RJ, Murphy WJ, Monjazeb AM
The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.
PMID: 30420753 [PubMed - as supplied by publisher]
Subclinical cytomegalovirus infection associates with altered host immunity, gut microbiota and vaccine responses.
J Virol. 2018 Apr 18;:
Authors: Santos Rocha C, Hirao LA, Weber MG, Méndez-Lagares G, Chang WLW, Jiang G, Deere JD, Sparger EE, Roberts J, Barry PA, Hartigan-O'Connor DJ, Dandekar S
Subclinical viral infections (SVI) including cytomegalovirus (CMV) are highly prevalent in humans, resulting in life-long persistence. However, the impact of SVI on the interplay between the host immunity and gut microbiota in the context of environmental exposures is not well defined. We utilized the preclinical nonhuman primate (NHP) model consisting of SVI-free (SPF) rhesus macaques and compared them to the animals with SVI (non-SPF) acquired through natural exposure and investigated the impact of SVI on immune cell distribution and function as well as on gut microbiota. These changes were examined in animals housed in the outdoor environment as compared to the controlled indoor environment. We report that SVI are associated with altered immune cell subsets and gut microbiota composition in animals housed in the outdoor environment. Non-SPF animals harbored a higher proportion of potential butyrate-producing Firmicutes and higher numbers of lymphocytes, effector T cells and cytokine-producing T cells. Surprisingly, these differences diminished following their transfer to the controlled indoor environment, suggesting that non-SPFs had increased responsiveness to environmental exposures. An experimental infection of indoor SPF animals with CMV resulted in an increased abundance of butyrate-producing bacteria, validating that CMV enhanced colonization of butyrate-producing commensals. Finally, non-SPF animals displayed lower antibody responses to influenza vaccination as compared to SPF animals. Our data show that subclinical CMV infection heightens host immunity and gut microbiota changes in response to environmental exposures. This may contribute to the heterogeneity in host immune response to vaccines and environmental stimuli at the population level.IMPORTANCE Humans harbor several latent viruses that modulate host immunity and commensal microbiota, thus introducing heterogeneity in their responses to pathogens, vaccines and environmental exposures. Most of our understanding of the effect of CMV on the immune system is based on studies of children acquiring CMV or of immune-compromised humans with acute or reactivated CMV infection or in ageing individuals. The experimental mouse models are genetically inbred and are completely adapted to the indoor laboratory environment. In contrast, nonhuman primates are genetically outbred and are raised in the outdoor environment. Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota, which is evident only in the outdoor environment but not in the indoor environment. The significance of this study is in highlighting the impact of SVI on enhancing host immune susceptibility to environmental exposures and immune heterogeneity.
PMID: 29669841 [PubMed - as supplied by publisher]
HIV latency is reversed by ACSS2-driven histone crotonylation.
J Clin Invest. 2018 Feb 19;:
Authors: Jiang G, Nguyen D, Archin NM, Yukl SA, Méndez-Lagares G, Tang Y, Elsheikh MM, Thompson GR, Hartigan-O'Connor DJ, Margolis DM, Wong JK, Dandekar S
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.
PMID: 29457784 [PubMed - as supplied by publisher]
IL-21 Therapy Controls Immune Activation and Maintains Antiviral CD8(+) T Cell Responses in Acute Simian Immunodeficiency Virus Infection.
AIDS Res Hum Retroviruses. 2017 Nov;33(S1):S81-S92
Authors: Méndez-Lagares G, Lu D, Merriam D, Baker CA, Villinger F, Van Rompay KKA, McCune JM, Hartigan-O'Connor DJ
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replicate during acute infection in lymphocytes of the gastrointestinal tract, before disseminating systemically. Localized replication and associated loss of gut-resident CD4(+) T cells occur regardless of the portal of entry of the virus (e.g., intravenous vs. rectal). Thus, HIV and SIV are tropic for gut tissue, and their pathogenesis requires the special environment of the intestine. T helper 17 (Th17) cells are important contributors to microbial defense in the gut that are vulnerable to HIV infection and whose loss is associated with translocation of microbial products to the systemic circulation, leading to chronic immune activation and disease progression. Interleukin (IL)-21 promotes differentiation and survival of Th17 cells and stimulates CD8(+) T cell function. By promoting Th17 cell survival, IL-21 could limit bacterial translocation and immune activation in the setting of acute or rebounding HIV/SIV disease. In this study, we tested the effect of recombinant IL-21-IgFc treatment, given at the time of infection, on SIVmac251 infection. We found that rIL-21-IgFc decreases immune activation and maintains effective antiviral responses by CD8(+) T cells in blood, but this maintenance is not associated with lower viral loads. rIL-21-IgFc treatment also did not generally support Th17 cell populations, but Th17 cells remained strongly and independently associated with control of plasma viremia. For example, the single animal exhibiting greatest control over viremia in our study also manifested the highest levels of IL-21 in plasma, Th17 cell maintenance in blood, and Th17 cells in intestinal tissue. These findings provide rationale for further exploration of IL-21 treatment as a support for host CD8(+) T cell responses in HIV cure strategies.
PMID: 29140110 [PubMed - in process]
Depletion of gut-resident CCR5+ cells for HIV cure strategies.
AIDS Res Hum Retroviruses. 2017 Sep 17;
Authors: Merriam DP, Chen C, Mendez-Lagares G, Rogers K, Michaels A, Yan J, Casaz P, Reimann K, Villenger F, Hartigan-O'Connor DJ
The HIV reservoir forming at the earliest stages of infection is likely composed of CCR5+ cells, because these cells are the targets of transmissible virus. Restriction of the CCR5+ reservoir, particularly in gut, may be needed for subsequent cure attempts. Strategies for killing or depleting CCR5+ cells have been described, but none have been tested in vivo in non-human primates and the extent of achievable depletion from tissues is not known. Here we investigate the efficacy of two novel cytotoxic treatments for targeting and eliminating CCR5+ cells in young rhesus macaques. The first, an immunotoxin consisting of the endogenous CCR5 ligand RANTES fused with Pseudomonas exotoxin (RANTES-PE38), killed CCR5+ lamina propria lymphocytes (LPLs) ex vivo, but had no detectable effect on CCR5+ LPLs in vivo. The second, a primatized bispecific antibody for CCR5 and CD3, depleted all CCR5+ cells from blood and the vast majority of such cells from the colonic mucosa (60-96% of CD4+CCR5+). Absence of CCR5-expressing cells from blood endured for at least one week, while CCR5+ cells in colon were substantially replenished over the same time span. These data open an avenue to investigation of combined early ART treatment and CCR5+ reservoir depletion for cure of HIV-infected infants.
PMID: 28918646 [PubMed - as supplied by publisher]
Persistent effects of early infant diet and associated microbiota on the juvenile immune system.
Gut Microbes. 2015 Jul 4;6(4):284-9
Authors: Narayan NR, Méndez-Lagares G, Ardeshir A, Lu D, Van Rompay KK, Hartigan-O'Connor DJ
Early infant diet has significant impacts on the gut microbiota and developing immune system. We previously showed that breast-fed and formula-fed rhesus macaques develop significantly different gut microbial communities, which in turn are associated with different immune systems in infancy. Breast-fed animals manifested greater T cell activation and proliferation and harbored robust pools of T helper 17 (TH17) cells. These differences were sustained throughout the first year of life. Here we examine groups of juvenile macaques (approximately 3 to 5 y old), which were breast-fed or formula-fed in infancy. We demonstrate that juveniles breast-fed in infancy maintain immunologic differences into the fifth year of life, principally in CD8(+) memory T cell activation. Additionally, long-term correlation networks show that breast-fed animals maintain persistent relationships between immune subsets that are not seen in formula-fed animals. These findings demonstrate that infant feeding practices have continued influence on immunity for up to 3 to 5 y after birth and also reveal mechanisms for microbial modulation of the immune system.
PMID: 26177107 [PubMed - in process]
Breast-fed and bottle-fed infant rhesus macaques develop distinct gut microbiotas and immune systems.
Sci Transl Med. 2014 Sep 3;6(252):252ra120
Authors: Ardeshir A, Narayan NR, Méndez-Lagares G, Lu D, Rauch M, Huang Y, Van Rompay KK, Lynch SV, Hartigan-O'Connor DJ
Diet has a strong influence on the intestinal microbiota in both humans and animal models. It is well established that microbial colonization is required for normal development of the immune system and that specific microbial constituents prompt the differentiation or expansion of certain immune cell subsets. Nonetheless, it has been unclear how profoundly diet might shape the primate immune system or how durable the influence might be. We show that breast-fed and bottle-fed infant rhesus macaques develop markedly different immune systems, which remain different 6 months after weaning when the animals begin receiving identical diets. In particular, breast-fed infants develop robust populations of memory T cells as well as T helper 17 (TH17) cells within the memory pool, whereas bottle-fed infants do not. These findings may partly explain the variation in human susceptibility to conditions with an immune basis, as well as the variable protection against certain infectious diseases.
PMID: 25186175 [PubMed - indexed for MEDLINE]
Monocyte activation by interferon α is associated with failure to achieve a sustained virologic response after treatment for hepatitis C virus infection.
J Infect Dis. 2014 May 15;209(10):1602-12
Authors: Hartigan-O'Connor DJ, Lin D, Ryan JC, Shvachko VA, Cozen ML, Segal MR, Terrault NA, Lanier LL, Manos MM, McCune JM
BACKGROUND: Interferon α (IFN-α) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-α differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells.
METHODS: We examined responses to in vitro IFN-α treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN. We analyzed the variable responses of antigen-presenting cell subsets to drug.
RESULTS: We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-α than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-α, a factor that was second in importance only to IL28B genotype in its association with SVR.
CONCLUSIONS: These results suggest that interindividual variability in the response of monocytes to IFN-α is an important determinant of treatment success with IFN-α-based regimens.
PMID: 24325966 [PubMed - indexed for MEDLINE]
IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia.
Int Immunol. 2013 Aug;25(8):471-83
Authors: Miller CN, Hartigan-O'Connor DJ, Lee MS, Laidlaw G, Cornelissen IP, Matloubian M, Coughlin SR, McDonald DM, McCune JM
IL-7 is a required factor for T-cell homeostasis. Because of low expression levels and poor reagent availability, the cellular sources of IL-7 have proven challenging to characterize. In this study, we describe a reporter mouse in which enhanced GFP is expressed from the endogenous Il7 locus. We show that IL-7 is produced by lymphatic endothelial cells (LECs) distributed throughout the systemic lymphatic vasculature as well as by fibroblastic reticular cells, and that phosphorylation of STAT5 in lymphocytes is higher in lymphatics than in blood. Furthermore, in nodes depleted of lymphocytes, Il7 transcription is increased in stromal but not in myeloid subsets. These data support recent findings that lymphocyte homeostasis is influenced by access to secondary lymphoid organs and point to LECs as an important in vivo source of IL-7, bathing trafficking immune cells under both resting and lymphopenic conditions.
PMID: 23657000 [PubMed - indexed for MEDLINE]
SIV replication in the infected rhesus macaque is limited by the size of the preexisting TH17 cell compartment.
Sci Transl Med. 2012 May 30;4(136):136ra69
Authors: Hartigan-O'Connor DJ, Abel K, Van Rompay KK, Kanwar B, McCune JM
The mechanisms by which some HIV-infected subjects resist disease progression, whereas others progress rapidly, are incompletely understood. Viral and host genetic factors, such as nef deletions and major histocompatibility complex alleles, explain a portion of the observed variability. However, it has been difficult to identify host immune functions that may be present before infection and that allow resistance to lentiviral disease progression. Here, we show that simian immunodeficiency virus replication in the infected rhesus macaque is limited by the size of the preexisting T helper 17 (T(H)17) cell compartment: Animals with a high representation of such cells in blood and intestinal tissue before infection experienced peak and set-point viral loads about one log unit lower than those with a lower representation of T(H)17 cells. Reciprocally, treatment of macaques with interleukin-2 and granulocyte colony-stimulating factor before infection led to depletion of T(H)17 cells, reduction of the ratio between T(H)17 cells and CD3(+)CD4(+)CD25(+)CD127(low) regulatory T cells, and higher viral loads for 6 months after infection. These results demonstrate that the composition of the host immune system before infection has an influence on the course of disease after infection. Furthermore, to the extent that this influence shapes and interacts with T cell-mediated responses to virus, our findings provide a new framework for understanding interindividual variation in responses to therapies and vaccines against HIV.
PMID: 22649090 [PubMed - indexed for MEDLINE]
Th17 cells and regulatory T cells in elite control over HIV and SIV.
Curr Opin HIV AIDS. 2011 May;6(3):221-7
Authors: Hartigan-O'Connor DJ, Hirao LA, McCune JM, Dandekar S
PURPOSE OF REVIEW: We present current findings about two subsets of CD4+ T cells that play an important part in the initial host response to infection with the HIV type 1: those producing IL-17 (Th17 cells) and those with immunosuppressive function (CD25+FoxP3+ regulatory T cells or T-reg). The role of these cells in the control of viral infection and immune activation as well as in the prevention of immune deficiency in HIV-infected elite controllers will be examined. We will also discuss the use of the simian immunodeficiency virus (SIV)-infected macaque model of AIDS to study the interplay between these cells and lentiviral infection in vivo.
RECENT FINDINGS: Study of Th17 cells in humans and nonhuman primates (NHPs) has shown that depletion of these cells is associated with the dissemination of microbial products from the infected gut, increased systemic immune activation, and disease progression. Most impressively, having a smaller Th17-cell compartment has been found to predict these outcomes. T-reg have been associated with the reduced antiviral T-cell responses but not with the suppression of generalized T cell activation. Both cell subsets influence innate immune responses and, in doing so, may shape the inflammatory milieu of the host at infection.
SUMMARY: Interactions between Th17 cells, T-reg, and cells of the innate immune system influence the course of HIV and SIV infection from its earliest stages, even before the appearance of adaptive immunity. Such interactions may be pivotal for elite control over disease progression.
PMID: 21399494 [PubMed - indexed for MEDLINE]
Development of cytomegalovirus (CMV) immune recovery uveitis is associated with Th17 cell depletion and poor systemic CMV-specific T cell responses.
Clin Infect Dis. 2011 Feb 1;52(3):409-17
Authors: Hartigan-O'Connor DJ, Jacobson MA, Tan QX, Sinclair E, Studies of Ocular Complications of AIDS Research Group
BACKGROUND: the immune reconstitution inflammatory syndromes (IRIS) are a spectrum of inflammatory conditions associated with opportunistic infections and occurring in approximately16% of human immunodeficiency type 1 (HIV-1)-infected patients given antiretroviral therapy. It has been proposed that these conditions are linked by a dysregulated immune system that is prone to exaggerated responses. However, immunologic studies have been limited by the availability of longitudinal samples from patients with IRIS and appropriate matched control subjects. Cytomegalovirus (CMV) immune recovery uveitis (IRU) is an IRIS occurring in up to 38% of patients with CMV retinitis. Although the pathologic immune responses occur in the eye, immune dysregulation that allows for development of pathologic responses is presumably caused by faulty systemic immune cell reconstitution.
METHODS: we examined CMV-specific T cell responses, regulatory T (T(reg)) cell function and polyclonal T cell responses, including IL-17 production, in 25 patients with CMV IRU and 49 immunorestored control subjects with CMV retinitis who did not develop IRU.
RESULTS: patients with CMV IRU had poor CMV-specific CD4(+) T cell responses, as compared with control subjects, whereas CD8(+) T cell responses were comparable. Patients with CMV IRU were characterized by smaller numbers of circulating Th17 cells. Deficiency in anti-CMV responses was not associated with differences in T(reg) cell function.
CONCLUSIONS: the T(reg) cell compartment is intact in patients with CMV IRU, and these patients do not develop exaggerated systemic CMV-specific or polyclonal immune responses. Cases are instead characterized by more profound depletion of Th17 cells and poor antiviral immune responses. CMV IRU may be most likely to develop in persons experiencing the greatest degree of immune dysfunction before initiating highly active antiretroviral therapy.
PMID: 21189271 [PubMed - indexed for MEDLINE]
The human fetal immune response to hepatitis C virus exposure in utero.
J Infect Dis. 2011 Jan 15;203(2):196-206
Authors: Babik JM, Cohan D, Monto A, Hartigan-O'Connor DJ, McCune JM
BACKGROUND: Although the rate of mother-to-child transmission of hepatitis C virus (HCV) is low, the effect of HCV exposure in utero on the fetal immune system is unknown.
METHODS: Umbilical cord blood was obtained from 7 neonates born to HCV-seropositive, HCV RNA-positive women and 8 neonates born to HCV-seronegative women. Cord blood mononuclear cells were analyzed by immunophenotyping and by intracellular cytokine staining after HCV-specific and polyclonal stimulation. Plasma was analyzed for anti-HCV immunoglobulin M (IgM), cytokine/granzyme concentrations, and indoleamine 2,3-dioxygenase (IDO) activity.
RESULTS: HCV-exposed neonates had significantly lower levels of regulatory T cells expressing HLA-DR, lower CD4(+) and CD8(+) T cell activation, and lower plasma levels of pro-inflammatory markers than did controls. However, CD4(+) and CD8(+) T cells from HCV-exposed neonates had higher IFN-γ production in response to polyclonal stimulation than did T cells from controls. IDO activity was similar between groups. No HCV-specific T cell responses or anti-HCV IgM were detected in any neonates.
CONCLUSIONS: HCV-exposed neonates showed a relative suppression of immune activation and pro-inflammatory markers, which was counterbalanced by an increased production capacity for IFN-γ. These results suggest that HCV encounters the fetal immune system in utero, and alters the balance between suppressive and pro-inflammatory responses.
PMID: 21288819 [PubMed - indexed for MEDLINE]