Current Projects:

Research in the Nolz Laboratory is broadly focused on the cellular and molecular mechanisms that regulate the activation, differentiation, trafficking, and overall function of T cells during viral, bacterial, and parasitic infections.

Mechanisms that control the trafficking of T cells into non-lymphoid tissues

Trafficking of T cells out of the circulation and into various tissues is a highly orchestrated process involving multiple receptor – ligand interactions. The selectin family of proteins (L-, P-, and E-selectin) play a critical role in regulating immune cell trafficking and facilitate the initial interactions between T cells and the vascular endothelium prior to chemokine-mediated signaling and integrin activation. Ligands for selectins require post-translational glycosylation to become functional and both CD8+ and CD4+ T cells exhibit dynamic regulation of the enzymes that are responsible for generating these O-linked glycan structures. We have investigated extensively the mechanisms that regulate core 2 O-glycan synthesis in memory CD8+ T cells, thereby allowing these cells to generate ligands for the vascular adhesion molecules P- and E-selectin to promote extravasation into non-lymphoid tissues. Notably, we have found that the capacity to synthesize core 2 O-glycans is primarily a feature of central memory CD8+ T cells, and not effector memory T cells. We are currently investigating the transcriptional and enzymatic mechanisms that control O-glycan synthesis in both CD8+ and CD4+ T cells, thereby dictating the tissue-trafficking capacity of these cells in vivo during infections or other inflammatory events.

Nolz JC, Harty JT - "IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking." J Clin Invest. 2014 Mar 3;124(3):1013-26

 Osborn JF*, Mooster JL*, Hobbs SJ, Munks MW, Barry C, Harty JT, Hill AB, Nolz JC *These Authors Contributed Equally - "Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8+ T cells." Sci Immunol. 2017 Oct 13;2(16)

 Osborn JF, Hobbs SJ, Mooster JL, Khan TN, Kilgore AM, Harbour JC, Nolz JC - "Central memory CD8+ T cells become CD69+ tissue resident during viral skin infection independent of CD62L-mediated lymph node surveillance." PLOS Pathog. 2019 Mar 15;15(3)

Figure one: Illustration comparing T cell trafficking through vascular endothelium in three stages: rolling/tehtering, activation and firm adhesion/attachment.
Molecular interactions dictating trafficking of T cells into (A) lymph nodes through high endothelial venules or (B) inflamed tissues through vascular endothelium.

Figure three: Diagram entitled P- and E- Selectin Binding,  illustrates the effects of antigen encounter on CD8+ T cells, the partial loss of these effects over time, and the recurrence of these effects with exposure to IL-15 during an inflammatory challenge.
Naive CD8+ T cells express core 1 O-glycans, but not core 2 O-glycans and cannot bind to P- or E-selectin. Following antigen encounter, CD8+ T cells rapidly express extended core 2 O-glycans, bind to P- and E-selectin, and undergo chromatin remodeling at the Gcnt1 gene locus. Over time, most memory CD8+ T cells lose expression of core 2 O-glycans and cannot bind to P- or E-selectin during the steady state (non-inflamed) environment. However, the Gcnt1 gene locus remains in an open chromatin configuration and, following exposure to IL-15 during an inflammatory challenge, will rapidly generate core 2 O-glycans, bind to both P- and E-selectin, and efficiently localize to inflamed tissue.

Differentiation of tissue-resident memory T cells within non-lymphoid tissue microenvironments

Tissue-resident memory T cells are permanently positioned within non-lymphoid tissues to provide a first-line of defense against pathogen invasion at environmental barriers, but the mechanisms that govern the development of this unique T cell population are largely unknown. To study the formation of tissue-resident memory T cells in the skin, we utilize epicutaneous poxvirus infections to study the cellular and molecular mechanisms that promote (or inhibit) tissue-resident memory T cell differentiation. Using skin infections with Vaccinia viruses expressing model antigens, we were the first to conclusively demonstrate that local antigen recognition within tissue microenvironments significantly promotes tissue-resident memory T cell formation by ~50 fold.  In addition, we have recently found that circulating memory CD8+ T cells are recruited into the skin following local activation of tissue-resident CD8+ T cells, and then become tissue-residents in an antigen-specific manner.  Thus, a major goal of the laboratory is to determine mechanistically how engagement of the T cell receptor in combination with other microenvironmental factors promotes the differentiation of tissue-resident T cells within non-lymphoid tissues such as the skin during viral infection.

Khan TN, Mooster JL, Kilgore AM, Osborn JF, Nolz JC - "Local antigen in non-lymphoid tissue promotes resident memory CD8+ T cell formation during viral infection." J Exp Med. 2016 May 30;213(6):951-66

Hobbs SJ, Nolz JC - "Targeted expansion of tissue-resident CD8+ T cells to boost cellular immunity in the skin." Cell Rep. 2019 Dec 3;29(10):2990-2997

Jeff Nolz - Nolz Lab Image for 2nd project - Image 1
Following viral skin infection, antigen-specific CD8+ T cells become activated in the draining lymph node, undergo proliferative expansion and enter the circulation. Some of these recently activated effector CD8+ T cells extravasate across activated vascular endothelium and into the skin. Once in the skin, CD8+ T cells migrate to the site of viral infection, exhibit effector functions to accelerate viral clearance, and differentiate into tissue-residents.

Jeff Nolz - Nolz Lab Image for 2nd project - Image 2
Within the skin microenvironment, antigen recognition along with additional factors including TGF-beta promote the differentiation of effector CD8+ T cells into long-lived tissue-resident memory T cells.

T cell activation, differentiation, and function during cutaneous and visceral leishmaniasis

We have recently begun investigating the mechanisms that regulate the antigen-specific CD4+ T cell response during both cutaneous and visceral leishmaniasis. Our preliminary data have shown that antigen-specific CD4+ T cells expand and remain highly functional during cutaneous leishmaniasis, but become functionally exhausted and produce IL-10 during a visceral infection. Thus, we are currently investigating 1) whether subunit vaccination strategies alter the extent of T cell exhaustion during visceral leishmaniasis 2) the differentiation and transcriptional profiles of antigen-specific CD4+ T cells responding to either cutaneous or visceral leishmaniasis and, 3) whether targeted immunotherapy during visceral leishmaniasis restores antigen-specific CD4+ T cell function to accelerate parasite clearance.

Hobbs SJ, Harbour JC, Yates PA­­, Ortiz, D, Landfear SM, Nolz JC - "Vaccinia virus vectors targeting peptides for MHC-II presentation to CD4+ T cells." Immunohorizons. 2020 Jan 2;4(1):1-13