Alternative pathways for the development of lymphoid structures in humans

Area of Science:

• Immunology
• Developmental Biology
• Human Genetics

Background:

• Lymphoid tissue inducer (LTi) cells are crucial for secondary lymphoid organ (SLO) development in mice.
• Human severe combined immunodeficiencies (SCIDs) due to JAK3 or gamma-chain (γc) deficiency involve absent T cells, NK cells, innate lymphoid cells (ILCs), and likely LTi cells.
• Allogeneic stem cell transplantation (HSCT) in some SCID patients results in donor T cell engraftment with host-derived leukocytes.

Purpose of the Study:

• To investigate the presence and location of SLOs in humans with γc-SCID after HSCT.
• To determine if SLOs in these patients are dependent on LTi cells.
• To explore potential LTi cell-independent mechanisms for SLO formation.

Main Methods:

• Magnetic Resonance Imaging (MRI) was used to identify SLOs in nine patients 16-44 years post-HSCT.
• Postmortem examination of a child with γc-SCID 3.5 months after HSCT was conducted.
• Analysis of lymphoid structures for the presence of RAR-related orphan receptor-positive LTi cells.

Main Results:

• SLOs were exclusively found in abdominal areas draining the intestinal tract in nine patients after HSCT.
• Postmortem examination revealed thymic corticomedullary differentiation, splenic T cell zones, and an appendix, but absent lymph nodes and Peyer patches.
• Tertiary lymphoid organs were present in the lung, and no LTi cells were detected in existing lymphoid structures.

Conclusions:

• While LTi cells are essential for most human SLO genesis, the appendix and gut-draining SLOs can form through LTi cell-independent pathways.
• Tertiary lymphoid organs may also develop independently of LTi cells.
• These findings challenge the universal requirement of LTi cells for all lymphoid organogenesis in humans.