Research

Differences between the fetal, neonatal, and adult immune system 

The mammalian immune system develops progressively during ontogeny. In both mice and humans, the types of immune cells that develop in infants differ from those that develop in adulthood. Our goal is to understand the differences between the immune cells that develop preferentially in fetal, neonatal, and adult life, and determine the functional impact of these differences in promoting host immunity or immunopathology.

Recently, we have identified, in mouse models, lineages of innate-like tissue-resident B lymphocytes and macrophages that develop in the fetus (but not adults) independently of the long-term hematopoietic stem cells (LT-HSC). We are also using humanized mice to investigate the development and function of these innate-like tissue-resident B lymphocytes and macrophages in humans, during both infancy and adulthood.

Current research projects:

  • HSC-independent hematopoiesis
  • Tissue-resident lymphocytes
  • Tissue-resident macrophages

Read more about these projects in the sections below.

HSC-independent hematopoiesis

The current paradigm posits that a single hematopoietic stem cell (HSC) regenerates all components of the immune system. As a result, today more than 20,000 HSC transplantations are performed every year to restore immunity in immune-compromised patients (e.g., to treat lymphomas, leukemias, myelomas, and immunodeficiency disorders) (Pasquini and Zhu, 2014).

Ghosn EE et al.

However, our recent studies in murine HSC transplantation (Ghosn et al., PNAS 2012; Ghosn et al., Ann. N. Y. Acad. Sci. 2015; and Ghosn et al., 2016 Stem Cell Reports) have challenged this broadly accepted paradigm and establish a novel concept of HSC-independent hematopoiesis (Figure 3). In essence, we showed that long-term (LT)-HSCs, purified from fetal liver and adult bone marrow, selectively fail to regenerate B-1a, a subset of tissue-resident lymphocytes that secrete most of the natural antibodies in serum and is required for protection against Pneumonia, Influenza, and other infectious diseases.

Similarly, data from our LT-HSC transplantations combined with in vivo lineage tracing studies show that certain tissue-resident macrophages, such as brain microglia, originate independently of LT-HSCs. Taken together, these findings now overtly challenge the broadly accepted paradigm that HSC transplantation fully regenerates all components of the immune system.

Ghosn EE et al.

Because about 20% of patients die post-HSC transplantation due to infectious diseases, our data showing that murine HSC transplantation fails to reconstitute a key component of the humoral immune system open the broad question of whether humans, like mice, generate tissue-resident B lymphocytes and macrophages (and other hematopoietic lineages) independently of HSCs and, if so, whether these immune cells play critical roles that may help protect HSC-transplanted patients from subsequent infections and other post-transplant diseases. Our current research projects are tackling these and other related questions. 

Ghosn EE et al

Determining the developmental pathway(s) of HSC-independent and HSC-dependent immune cells will provide a richer view of the functionality of the immune system and the ways by which evolution has addressed different needs encountered at different developmental stages, from fetal life through adulthood. At a minimum, these findings change our current understanding of the developmental landscape of the immune system by challenging the notion that LT-HSCs fully reconstitute all components of the immune system.

Tissue-resident lymphocytes

Tissue-resident immune cellsWe are interested in understanding the development and function of tissue-resident lymphocytes, in contrast to circulating blood lymphocytes. We have shown that tissue-resident B lymphocytes, such as innate-like B-1a cells, emerge early during fetal development independently of the LT-HSC and then migrate to take residence in serous cavities (i.e. pleural and peritoneal) where they surround the lung and intestinal mucosa. These tissue-resident B lymphocytes carry unique functions that are not performed by peripheral blood or follicular B lymphocytes.

Ghosn study

In vivo We propose that the development of HSC-independent lineages early in ontogeny represents an evolutionary strategy that ensures the development of an immune system carrying unique functions that are evolutionarily conserved and distinct from the functions of the adaptive immune system operating in adults.
Currently, we are studying the origin of murine tissue-resident lymphocytes during fetal hematopoiesis using in vivo lineage tracing models. We are also developing humanized mice to study the development and function of human tissue-resident B lymphocytes using human fetal and adult tissues. Mouse example

Tissue-resident macrophages

Peritoneal Macrophage
   
The myeloid lineage comprises several functionally and developmentally distinct subsets, including circulating monocytes, and tissue-resident macrophages. Several studies have shown that tissue-resident macrophages, but not circulating monocytes, emerge from the yolk sac during embryogenesis independent of the LT-HSC. Brain and skin resident macrophages (i.e., microglia and Langerhans cells, respectively) emerge at around embryonic day 8 (E8) in a region of the yolk sac known as the blood island, even before the development of the first definitive LT-HSC. The yolk sac-derived (HSC-independent) macrophages then migrate and take long-term residence in the brain and skin of the developing embryo.
 
Recently, we have identified and characterized two functionally distinct subsets of tissue-resident peritoneal macrophages named small (SPM) and large (LPM) peritoneal macrophages. Currently, we are studying their origin and functional relationship with other tissue-resident macrophages, such as brain microglia, liver Kupffer, and skin Langerhans cells.
   
Ghosn Figures 1 & 2

Ghosn Lab

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We are located in Emory University's new Health Sciences Research Building (HSRB - 1760 Haygood Drive NE, Atlanta, GA 30322), 2nd floor, Room E240. Our laboratory is located in HSRB, Room E269. If you have any questions, please contact Dr. Ghosn at eghosn@emory.edu or (404) 712-3211.